Alternative titles; symbols
HGNC Approved Gene Symbol: PSEN1
SNOMEDCT: 230270009; ICD10CM: G31.0, G31.01; ICD9CM: 331.1, 331.11;
Cytogenetic location: 14q24.2 Genomic coordinates (GRCh38): 14:73,136,417-73,223,691 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q24.2 | ?Acne inversa, familial, 3 | 613737 | Autosomal dominant | 3 |
| Alzheimer disease, type 3 | 607822 | Autosomal dominant | 3 | |
| Alzheimer disease, type 3, with spastic paraparesis and apraxia | 607822 | Autosomal dominant | 3 | |
| Alzheimer disease, type 3, with spastic paraparesis and unusual plaques | 607822 | Autosomal dominant | 3 | |
| Cardiomyopathy, dilated, 1U | 613694 | Autosomal dominant | 3 | |
| Dementia, frontotemporal | 600274 | Autosomal dominant | 3 | |
| Pick disease | 172700 | Autosomal dominant | 3 |
The PSEN1 gene encodes presenilin-1, which forms the catalytic component of gamma-secretase. Gamma-secretase is responsible for proteolytic cleavage of amyloid precursor protein (APP; 104760) and NOTCH receptor proteins (see 190198). Gamma-secretase is a multiprotein complex consisting of PSEN1 or its homolog PSEN2 (600759), nicastrin (605254), APH1 (see APH1A, 607629), and PEN2 (PSENEN; 607632) (summary by De Strooper, 2003; Chau et al., 2012).
By linkage mapping, Sherrington et al. (1995) defined a minimal cosegregating region containing the candidate gene for early-onset Alzheimer disease type 3 (AD3; 607822), which had been linked to chromosome 14q24.3. Of 19 different transcripts isolated, 1 transcript, designated S182 by them, corresponded to a novel gene that encoded a 467-amino acid protein. Human and murine amino acid sequences shared 92% identity. Northern blot analysis identified a major 3-kb transcript expressed in most regions of the human brain and in several peripheral tissues. Structural analysis predicted an integral membrane protein with at least 7 transmembrane helical domains.
The Alzheimer's Disease Collaborative Group (1995) isolated full-length cDNA clones for what they referred to as the PS1 gene. Contrary to previous mapping data, they found that the gene maps just telomeric to D14S77. The location at the 5-prime end of a specific YAC enabled them to determine that the gene is oriented 5-prime/3-prime centromere-telomere. Evidence for alternative splicing of the gene was found.
Thinakaran et al. (1996) observed a polypeptide of approximately 43 kD in cells transfected with full-length human PS1 cDNA. Using 2 highly specific antibodies against nonoverlapping epitopes of presenilin-1, they demonstrated that the preponderant PS1-related species that accumulate in cultured mammalian cells and in the brains of rodents, primates, and humans are approximately 27-kD N-terminal and about 17-kD C-terminal derivatives. Epitope mapping analysis showed that PS1 cleavage occurred between amino acids 260 and 320. In brains of transgenic mice expressing human PS1, the 17-kD and the 27-kD PS1 derivatives accumulate to saturable levels, and at about 1:1 stoichiometry, independent of transgene-derived mRNA. The authors concluded that PS1 is subject to endoproteolytic processing in vivo. In a British familial Alzheimer disease (FAD) pedigree, a PS1 variant with a deletion of amino acids 290 to 319 (delE9) (104311.0012) was not cleaved.
Rogaev et al. (1997) determined that alternative splicing produces several PSEN1 transcripts which encode distinct protein sequences; exon 9 is specifically removed from PSEN1 transcripts in leukocytes but not in most other tissues. PSEN1 transcripts are polyadenylated at 2 alternative sites.
Mercken et al. (1996) produced 7 monoclonal antibodies that react with 3 nonoverlapping epitopes on the N-terminal hydrophilic tail of PS1. The monoclonal antibodies can detect the full-size 47-kD PS1 and the more abundant 28-kD degradation product in membrane extracts from human brain and human cell lines. PC12 cells transiently transfected with PS1 constructs containing 2 different Alzheimer mutations, M146V (104311.0007) and A246E (104311.0003), failed to generate the 28-kD degradation product in contrast to PC12 cells transfected with wildtype PS1. Mercken et al. (1996) suggested that type 3 Alzheimer disease may be the result of impaired proteolytic processing of PS1.
Laudon et al. (2005) determined that 9 of the 10 hydrophobic domains (HDs) of human PS1 form transmembrane domains. The first hydrophilic loop is oriented toward the lumen of the endoplasmic reticulum (ER), whereas the N terminus and large hydrophilic loop, including HD7, are in the cytosol. The C terminus is localized to the luminal side of the ER. The catalytic aspartates, asp257 and asp385, are located within HD6 and HD8, respectively.
The Alzheimer's Disease Collaborative Group (1995) determined that the open reading frame of PS1 is encoded by 10 exons. They concluded that the PS2 gene (PSEN2; 600759), located on chromosome 1, has a very similar gene structure.
Rogaev et al. (1997) reported that the PSEN1 gene spans at least 60 kb and has 13 exons. The first 4 exons contain untranslated sequence, and exons 1 and 2 represent alternate transcription initiation sites.
By in situ hybridization to tissues, Kovacs et al. (1996) demonstrated that the expression patterns of PS1 and PS2 in the brain are similar to each other and that messages for both are primarily detectable in neuronal populations. Immunochemical analyses indicated that PS1 and PS2 are similar in size and localize to similar intracellular compartments, such as the endoplasmic reticulum and Golgi complex. Takashima et al. (1996) showed that in COS-7 cells overexpressing PS1, the protein is localized to cellular membranes: plasma, endoplasmic reticulum, and perinuclear. They observed that PS1 immunoreactivity in the plasma membrane is concentrated in regions of cell-cell contact, suggesting that PS1 may be a cell adhesion molecule.
Li et al. (1997) demonstrated that wildtype PS1 and PS2 localize to the nuclear membrane and associate with interphase kinetochores and centrosomes, and suggested that the proteins play a role in chromosome organization and segregation. Li et al. (1997) stated that PS1 and PS2 localization to the membranes of the endoplasmic reticulum and Golgi is not unexpected for overexpressed membrane proteins because these locations are the sites of their synthesis and processing. They developed specific PS1 and PS2 antibodies directed at the N-terminal and loop domains. They discussed a pathogenic mechanism for FAD in which mutant presenilins cause chromosome missegregation during mitosis, resulting in apoptosis and/or trisomy 21 mosaicism. An alternative hypothesis is that mutant presenilins not appropriately trafficked out of the endoplasmic reticulum may interfere with normal APP processing.
Page et al. (1996) described the anatomic distribution of PS1 in the brain and its expression in Alzheimer disease. Using in situ hybridization in the rat forebrain, they showed that PS1 mRNA expression is primarily in cortical and hippocampal neurons with less expression in subcortical structures, in a regional pattern similar to that of amyloid precursor protein APP695. Excitotoxic lesions led to loss of PS1 signal. A neuronal pattern of expression of PS1 mRNA was also observed in the human hippocampal formation. AD and control levels did not differ. PS1 was expressed to a greater extent in brain areas vulnerable to AD than in areas spared in AD; however, PS1 expression was not sufficient to mark vulnerable regions. Collectively, the data suggested to Page et al. (1996) that the neuropathogenic process consequent to PS1 mutations begins in neuronal cell populations.
Gamma-secretase Activity
PS1 and PS2 are important determinants of gamma-secretase activity responsible for proteolytic cleavage of amyloid precursor protein (APP; 104760) and NOTCH receptor proteins (see 190198). Gamma-secretase is a multiprotein complex consisting of PS1 or PS2, nicastrin (605254), APH1 (see APH1A; 607629), and PEN2 (PSENEN; 607632). See review by De Strooper (2003).
To clarify whether PS1, which has little or no homology to any known aspartyl protease, is itself a transmembrane aspartyl protease, a gamma-secretase cofactor, or helps to colocalize gamma-secretase and APP, Li et al. (2000) reported photoaffinity labeling of PS1 (and PS2) by potent gamma-secretase inhibitors that were designed to function as transition-state analog inhibitors directed to the active site of an aspartyl protease. Li et al. (2000) suggested that their observation indicates that PS1 (and PS2) may contain the active site of gamma-secretase. Interestingly, the intact, single-chain form of wildtype PS1 was not labeled by an active site-directed photoaffinity probe, suggesting that intact wildtype PS1 may be an aspartyl protease zymogen. Upon gel exclusion chromatography, solubilized gamma-secretase activity coeluted with PS1. Anti-PS1 antibody immunoprecipitated gamma-secretase activity from the solubilized gamma-secretase preparation. The authors interpreted the data as indicating that gamma-secretase activity is catalyzed by a PS1-containing macromolecular complex.
Kopan and Goate (2000) reviewed the evidence that presenilins are founding members of a novel class of aspartyl proteases that hydrolyze peptide bonds embedded within a membrane. The authors stated that although PS1 and PS2 both appear to be gamma secretases, it is not clear if the 2 enzymes normally have similar or different substrates, since they reside in different complexes. They proposed that the key to the regulation of cleavage may depend on the characterization of other proteins that are present in the high molecular weight complex that contains gamma-secretase activity.
Using coimmunoprecipitation and nickel affinity pull-down approaches, Lee et al. (2002) showed that nicastrin and presenilin heterodimers physically associated with APH1A and APH1B (607630) in vivo to form the gamma-secretase complex that is required for the intramembrane proteolysis of many membrane proteins, including APP and NOTCH. Francis et al. (2002) observed a reduction in the levels of processed presenilin and a reduction in gamma-secretase cleavage of beta-APP and Notch substrates after RNA-mediated interference assays that inactivated Aph1, Pen2, or nicastrin in cultured Drosophila cells. They concluded that APH1, PEN2, and nicastrin are required for the activity and accumulation of gamma-secretase. Using coimmunoprecipitation experiments, Steiner et al. (2002) also showed that PEN2 is a critical component of PSEN1/gamma-secretase and PSEN2/gamma-secretase complexes. They observed that the absence of Psen1 or both Psen1 and Psen2 in mice resulted in reduced PEN2 levels. Additionally, Steiner et al. (2002) reported that downregulation of PEN2 by RNA interference was associated with reduced presenilin levels, impaired nicastrin maturation, and deficient gamma-secretase complex formation.
Gamma-secretase activity requires the formation of a stable, high molecular mass protein complex that, in addition to the endoproteolyzed fragmented form of presenilin, contains essential cofactors including nicastrin, APH1, and PEN2. Takasugi et al. (2003) showed that Drosophila APH1 increases the stability of Drosophila presenilin holoprotein in the complex. Depletion of PEN2 by RNA interference prevented endoproteolysis of presenilin and promoted stabilization of the holoprotein in both Drosophila and mammalian cells, including primary neurons. Coexpression of Drosophila Pen2 with Aph1 and nicastrin increased the formation of presenilin fragments as well as gamma-secretase activity. Thus, Takasugi et al. (2003) concluded that APH1 stabilizes the presenilin holoprotein in the complex, whereas PEN2 is required for endoproteolytic processing of presenilin and conferring gamma-secretase activity to the complex.
Using Western blot analysis and immunogold electron microscopy, Pasternak et al. (2003) demonstrated that significant amounts of nicastrin, Psen1, and App colocalized with Lamp1 (153330) in the outer membranes of rat lysosomes. Furthermore, rat lysosomal membranes were enriched in acidic gamma-secretase activity that was precipitable with anti-nicastrin antibody.
Kaether et al. (2004) determined that the very C terminus of PS1 interacts with the transmembrane domain of nicastrin and may penetrate into the membrane. Deletion of the last amino acid of PS1 completely blocked gamma-secretase assembly and release of PS1 from the ER, suggesting that unincorporated PS1 is actively retained within the ER. Kaether et al. (2004) identified a hydrophobic stretch of amino acids within the PS1 C terminus, distinct from the nicastrin-binding site, that was required to retain unincorporated PS1 within the ER. Deletion of the retention signal resulted in release of PS1 from the ER and assembly of a nonfunctional gamma-secretase complex, suggesting that at least part of the retention motif is required for PS1 function.
Cai et al. (2006) showed that PSEN1, via its loop region, binds phospholipase D1 (PLD1; 602382) and recruits it to the Golgi/trans-Golgi network (TGN). Overexpression of PLD1 in mouse neuroblastoma (N2a) cells decreased gamma-secretase-mediated beta-amyloid generation, whereas downregulation of PLD1 increased beta-amyloid production. Further studies showed that PLD1 disrupted association of gamma-secretase protein components, independent of PLD1 catalytic activity. In a companion paper, Cai et al. (2006) found that overexpression of catalytically active PLD1 promoted generation of beta-amyloid-containing vesicles from the TGN. Although PLD1 enzymatic activity was decreased in N2a cells with FAD PSEN1 mutations, overexpression of wildtype PLD1, but not catalytically inactive PLD1, in these cells increased cell surface delivery of beta-amyloid at axonal terminals and rescued impaired axonal growth and neurite branching. The findings showed that PLD1 regulates intracellular trafficking of beta-amyloid, distinct from its effect on gamma-secretase activity.
Role in Beta-amyloid Production
Duff et al. (1996) demonstrated that transgenic mice overexpressing mutant, but not wildtype, presenilin-1 show a selective increase in brain A-beta-42(43). These results indicated that the presenilin mutations probably cause Alzheimer disease through a gain of deleterious function that increases the amount of the deposited A-beta-42(43) in the brain. While Davis et al. (1998) showed that there was no difference in amyloid deposition between wildtype mice and those with loss of 1 functional PS1 allele, Qian et al. (1998) showed that mice carrying the A246E mutation showed increased levels of A-beta-42(43), further supporting the gain-of-function hypothesis.
Citron et al. (1997) noted that several lines of evidence strongly supported the conclusion that progressive cerebral deposition of amyloid beta protein is a seminal event in familial Alzheimer disease pathogenesis. They carried out experiments to test the hypothesis that FAD mutations act by fostering deposition of amyloid beta protein particularly in the highly amyloidogenic 42-residue form described by Jarrett et al. (1993). In transfected cell lines, mutant PS1 and PS2 resulted in a highly significant increase in beta-amyloid-42. The PS2 Volga mutation (N141I; 600759.0001) led to a 6- to 8-fold increase in the production of total amyloid beta-42; none of the PS1 mutations had such a dramatic effect, suggesting an intrinsic difference in the effects of PS1 and PS2 mutations. Transgenic mice carrying mutant PS1 genes overproduced amyloid beta-42 in the brain, which was detectable at 2 to 4 months of age. Citron et al. (1997) stated that their combined in vitro and in vivo data clearly demonstrated that the FAD-linked presenilin mutations directly or indirectly altered the level of gamma-secretase, but not of alpha- or beta-secretase, resulting in increased amyloid beta-42 production which may lead to cerebral beta-amyloidosis and AD.
Scheuner et al. (1996) showed that conditioned media from fibroblasts or plasma of affected members of pedigrees with PS1/PS2-linked mutations show a significant increase in the ratio of A-beta-1-42(43)/A-beta-1-40 relative to unaffected family members. Borchelt et al. (1996) found that this ratio was uniformly elevated in the conditioned media of independent N2a (a stable mouse neuroblastoma) cell lines transfected with and expressing 3 FAD-linked PS1 variants relative to cells expressing similar levels of wildtype PS1. Similarly, they found that this ratio was elevated in brains of young transgenic mice coexpressing a chimeric APP- and FAD-linked PS1 variant compared with brains of transgenic mice expressing APP alone or coexpressing wildtype PS1 and APP. The authors concluded that these results support the view that mutations in PS1 cause AD by increasing the extracellular concentration of amyloid-beta peptides 1-42(43), which foster amyloid-beta deposition.
Point mutations in the PS1 gene result in a selective increase in the production of the amyloidogenic peptide amyloid-beta(1-42) by proteolytic processing of APP. The possible role of PS1 in normal APP processing was studied by De Strooper et al. (1998) in neuronal cultures derived from PS1-deficient mouse embryos. They found that cleavage by alpha- and beta-secretase of the extracellular domain of APP was not affected by the absence of PS1, whereas cleavage by gamma-secretase of the transmembrane domain of APP was prevented, causing C-terminal fragments of APP to accumulate and a 5-fold drop in the production of amyloid peptide. Pulse-chase experiments indicated that PS1 deficiency specifically decreased the turnover of the membrane-associated fragments of APP. Thus, PS1 appears to facilitate a proteolytic activity that cleaves the integral membrane domain of APP. The results indicated to the authors that mutations in PS1 that manifest clinically cause a gain of function, and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheimer disease.
As outlined earlier, accumulation of amyloid-beta protein in the cerebral cortex is an early and invariant event in the pathogenesis of Alzheimer disease. The final step in the generation of A-beta from APP is an apparently intramembranous proteolysis by gamma-secretase(s). The most common cause of familial Alzheimer disease is mutation of the genes encoding presenilins 1 and 2, which alters gamma-secretase activity to increase the production of the highly amyloidogenic A-beta-42 isoform. Moreover, deletion of presenilin-1 in mice greatly reduces gamma-secretase activity, indicating that presenilin-1 mediates most of the proteolytic event. Wolfe et al. (1999) reported that mutation of either of 2 conserved transmembrane (TM) aspartate residues in presenilin-1, asp257 (in TM6) and asp385 (in TM7), substantially reduced A-beta production and increased the amounts of the carboxy-terminal fragments of APP that are the substrates of gamma-secretase. They observed these effects in 3 different cell lines as well as in cell-free microsomes. Either of the asp-to-ala mutations also prevented the normal endoproteolysis of presenilin-1 in the TM6-TM7 cytoplasmic loop. In a functional presenilin-1 variant (carrying a deletion in exon 9; 104311.0012) that is associated with familial Alzheimer disease and which does not require this cleavage, the asp385-to-ala mutation still inhibited gamma-secretase activity. These results were taken to indicate that the 2 transmembrane aspartate residues are critical for both presenilin-1 endoproteolysis and gamma-secretase activity, and suggested that presenilin-1 either is a unique diaspartyl cofactor for gamma-secretase or is itself gamma-secretase, an autoactivated intramembranous aspartyl protease.
Russo et al. (2000) demonstrated that a peculiar form of beta-amyloid that is devoid of the first 10 amino acids accumulates in the brains of patients carrying PS1 mutations and is more abundant than in subjects affected by other types of Alzheimer disease. Russo et al. (2000) used immunoblotting to detect various A-beta species present in brain tissue from 17 subjects with sporadic AD, 11 with familial AD linked to mutation in the PS1 gene, 2 with familial AD linked to the V717I mutation in the APP gene, and 3 healthy controls. In the soluble fraction prepared from all the diseased brains, A-beta electrophoretically resolved into 3 bands of relative molecular mass of 4.5 kD, 4.2 kD, and 3.5 kD, which were not detectable in controls. The 4.5-kD species contains A-beta(1-40/42), the 4.2 kD species is A-beta(py3-42), and the 3.5 kD species is A-beta(4-42) and A-beta(py11-42). The smallest band is significantly more prominent in subjects carrying PS1 mutations than in those with sporadic AD or in those with a defective APP gene, indicating that amino-terminally truncated forms are increased in PS1 mutants. Russo et al. (2000) suggested that the overexpression of amino-terminally truncated amyloid beta species indicates that not only is cleavage by gamma-secretase affected by PS1 mutation, but that cleavage by beta-secretase is as well.
Wilson et al. (2002) analyzed the production of several forms of secreted and intracellular beta-amyloid forms in mouse cells lacking PS1, PS2, or both proteins. Although most amyloid beta species were abolished in PS1/PS2 -/- cells, the production of intracellular A-beta-42 generated in the endoplasmic reticulum/intermediate compartment was unaffected by the absence of these proteins, either singly or in combination. Wilson et al. (2002) concluded that production of this pool of amyloid beta occurs independently of PS1/PS2, and therefore, another gamma-secretase activity must be responsible for cleavage of APP within the early secretory compartments.
Phiel et al. (2003) showed that glycogen synthase kinase-3-alpha (GSK3A; 606784) is required for maximal production of the beta-amyloid-40 and -42 peptides generated from the amyloid precursor protein by presenilin-dependent gamma-secretase cleavage. In vitro, lithium, a GSK3A inhibitor, blocked the production of the beta-amyloid peptides by interfering with the gamma-secretase step. In mice expressing familial AD-associated mutations in APP and PSEN1, lithium reduced the levels of beta-amyloid peptides. Phiel et al. (2003) noted that GSK3A also phosphorylates the tau protein (MAPT; 157140), the principal component of neurofibrillary tangles in AD, and suggested that inhibition of GSK3A may offer a new therapeutic approach to AD.
Pitsi and Octave (2004) found that expression of PS1 in insect cells expressing the C-terminal fragment of human APP (C99) increased production of beta-amyloid and proportionally increased intracellular levels of C99. Using pulse-chase experiments, they showed that C99 accumulation resulted from increased C99 half-life. Inhibition of gamma-secretase activity did not alter the ability of PS1 to increase intracellular levels of C99, suggesting that binding of PS1 to C99 does not necessarily lead to its immediate processing. Pitsi and Octave (2004) concluded that PS1 contains a substrate docking site and that processing of C99 is spatiotemporally regulated.
Lleo et al. (2004) used a fluorescence resonance energy transfer-based assay (fluorescence lifetime imaging; FLIM) to analyze how NSAIDs influence APP-PSEN1 interactions. In vitro and in vivo, ibuprofen, indomethacin, or flurbiprofen, but not aspirin or naproxen, had an allosteric effect on the conformation of PSEN1, which changed the gamma-secretase activity on APP to increase production of the shorter beta-38 cleavage product.
Kumar-Singh et al. (2006) studied amyloid A-beta and APP processing for a set of 9 clinical PSEN mutations using an ELISA-based in vitro method. All mutations significantly increased the ratio of A-beta-42 to A-beta-40 in vitro by significantly decreasing A-beta-40 with accumulation of APP C-terminal fragments, a sign of decreased PSEN activity. A significant increase in absolute levels of A-beta-42 was observed for only half of the mutations tested. They also showed that age of onset of PSEN1-linked familial Alzheimer disease correlated inversely with the ratio of A-beta-42/A-beta-40 and absolute levels of A-beta-42, but directly with A-beta-40 levels. Together, the data of Kumar-Singh et al. (2006) suggested that A-beta-40 may be protective by perhaps sequestering the more toxic A-beta-42 and facilitating its clearance.
Using immunologic and biochemical assays, Hayashi et al. (2012) found that HIG1 (HIGD1A; 618623) bound the gamma-secretase complex on the mitochondrial membrane of SK-N-SH human neuroblastoma cells. Mutation analysis showed that a C-terminal region encompassing transmembrane domain-2 was required for interaction with gamma-secretase. Overexpression of HIG1 suppressed hypoxia-induced gamma-secretase activity and intracellular amyloid-beta production and thereby inhibited hypoxia-induced mitochondrial dysfunction. In contrast, knockdown of HIG1 caused enhanced mitochondrial gamma-secretase activity and mitochondrial dysfunction.
Role in Notch Signaling Pathway
Signaling through the Notch receptor proteins (see 190198), which is involved in crucial cell fate decisions during development, requires ligand-induced cleavage of Notch. This cleavage occurs within the predicted transmembrane domain, releasing the Notch intracellular domain (NICD), and is reminiscent of gamma-secretase-mediated cleavage of APP. Deficiency of presenilin-1 inhibits processing of APP by gamma-secretase in mammalian cells, and genetic interactions between Notch and PS1 homologs in C. elegans indicate that the presenilins may modulate the Notch signaling pathway. De Strooper et al. (1999) reported that in mammalian cells PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signaling pathway that is affected by PS1. Moreover, several gamma-secretase inhibitors blocked this same step in Notch processing, indicating that related protease activities are responsible for cleavage within the predicted transmembrane domains of Notch and APP. Thus, the targeting of gamma-secretase for the treatment of Alzheimer disease may risk toxicity caused by reduced Notch signaling.
Struhl and Greenwald (1999) showed that null mutations in the Drosophila presenilin gene abolish Notch signal transduction and prevent its intracellular domain from entering the nucleus. Furthermore, they provided evidence that presenilin is required for the proteolytic release of the intracellular domain from the membrane following activation of Notch by ligand. In Drosophila, Struhl and Adachi (2000) assayed the substrate requirements for presenilin-dependent processing of Notch and other type I transmembrane proteins in vivo. They found that presenilin-dependent cleavage does not depend critically on the recognition of particular sequences in these proteins, but rather on the size of the extracellular domain: the smaller the size, the greater the efficiency of cleavage. Hence, Notch, beta-APP, and perhaps other proteins may be targeted for presenilin-mediated transmembrane cleavage by upstream processing events that sever the extracellular domain from the rest of the protein.
Ye et al. (1999) described loss-of-function mutations in the Drosophila presenilin gene that caused lethal Notch-like phenotypes such as maternal neurogenic effects during embryogenesis, loss of lateral inhibition within proneural cell clusters, and absence of wing margin formation. They showed that presenilin is required for the normal proteolytic production of carboxy-terminal Notch fragments that are needed for receptor maturation and signaling, and that genetically it acts upstream of both the membrane-bound form and the activated nuclear form of Notch. The findings linked the role of presenilin in Notch signaling to its effect on amyloid production in Alzheimer disease.
Takahashi et al. (2000) found that Mesp2 (605195) initiates the establishment of rostrocaudal polarity by controlling 2 Notch signaling pathways. Initially, Mesp2 activates a Ps1-independent Notch signaling cascade to suppress Dll1 (see 602768) expression and specify the rostral half of the somite. Ps1-mediated Notch signaling is required to induce Dll1 expression in the caudal half of the somite. Therefore, Mesp2- and Ps1-dependent activation of Notch signaling pathways might differentially regulate Dll1 expression, resulting in the establishment of the rostro-caudal polarity of somites.
Ikeuchi and Sisodia (2003) showed that the Notch ligands Delta-1 (606582) and Jagged-2 (602570) are subject to presenilin-dependent, intramembranous gamma-secretase processing, resulting in the production of soluble intracellular derivatives. The authors also showed that the Delta-1 intracellular domain (DICD) that is generated by the gamma-cleavage is transported into the nucleus and likely plays a role in transcriptional events. The authors proposed that the Jagged-2 intracellular domain (JICD) would play a similar role.
Interactions with Cadherin Proteins
Zhang et al. (1998) showed that presenilin-1 forms a complex with beta-catenin (CTNNB1; 116806) in vivo that increases beta-catenin stability. Pathogenic mutations in the PS1 gene reduce the ability of presenilin-1 to stabilize beta-catenin and lead to increased degradation of beta-catenin in the brains of transgenic mice. Moreover, beta-catenin levels are markedly reduced in the brains of Alzheimer disease patients with PS1 mutations. Loss of beta-catenin signaling increases neuronal vulnerability to apoptosis induced by amyloid-beta precursor protein. Thus, mutations in the PS1 gene may increase neuronal apoptosis by altering the stability of beta-catenin, predisposing individuals to early-onset Alzheimer disease.
Kang et al. (2002) showed that PS1 functions as a scaffold that rapidly couples beta-catenin phosphorylation through 2 sequential kinase activities independent of the Wnt (see 164820)-regulated axin (603816)/CK1-alpha (600505) complex. Presenilin deficiency resulted in increased beta-catenin stability in vitro and in vivo by disconnecting the stepwise phosphorylation of beta-catenin, both in the presence and absence of Wnt stimulation. These findings highlighted an aspect of beta-catenin regulation outside of the canonical Wnt-regulated pathway and a function of presenilin separate from intramembrane proteolysis.
In MDCK cells, Georgakopoulos et al. (1999) found that PS1 accumulated at intercellular contacts where it colocalized with components of the cadherin-based adherens junctions. PS1 fragments formed complexes with E-cadherin (CDH1; 192090), beta-catenin, and alpha-catenin (CTNNA1; 116805), all components of adherens junctions. In confluent MDCK cells, PS1 formed complexes with cell surface E-cadherin; disruption of Ca(2+)-dependent cell-cell contacts reduced surface PS1 and the levels of PS1-E-cadherin complexes. PS1 overexpression in human kidney cells enhanced cell-cell adhesion. These data showed that PS1 incorporates into the cadherin/catenin adhesion system and regulates cell-cell adhesion. PS1 concentrates at intercellular contacts in epithelial tissue; in brain, it forms complexes with both E- and N-cadherin (114020) and concentrates at synaptic adhesions. That PS1 is a constituent of the cadherin/catenin complex makes that complex a potential target for PS1 mutations associated with familial Alzheimer disease.
PS1 interacts with beta-catenin and promotes its turnover through independent mechanisms. Consistent with this activity, Xia et al. (2001) reported that PS1 is important in controlling epidermal cell proliferation in vivo. PS1 knockout mice that were rescued through neuronal expression of a human PS1 transgene developed spontaneous skin cancers. PS1-null keratinocytes exhibited higher cytosolic beta-catenin and beta-catenin/lymphoid enhancer factor (LEF1; 153245)-mediated signaling. This effect could be reversed by reintroducing wildtype PS1, but not a PS1 mutant active in Notch processing but defective in beta-catenin binding. Nuclear beta-catenin protein can be detected in tumors. Elevated beta-catenin/LEF signaling is correlated with activation of its downstream target cyclin D1 (168461) and accelerated entry from G1 into S phase of the cell cycle. The findings demonstrated a function of PS1 in adult tissues, and suggested that deregulation of the beta-catenin pathway contributes to the skin tumor phenotype. Hartmann (2001) commented that PS1 has evolved 'from a mere AD-associated protein into a multifunctional maverick sitting at the heart of an expanding number of cellular signaling mechanisms.'
In rodent neuronal cell cultures, Marambaud et al. (2003) found that Psen1 promoted an epsilon-cleavage of N-cadherin, resulting in the production of a soluble cytosolic fragment termed N-Cad/CTF2. The activity was stimulated by NMDA receptor agonists. Further studies showed that N-Cad/CTF2 bound the transcription factor CREB-binding protein (CBP; 600140) in the cytosol and promoted its degradation through the ubiquitin-proteasome system, thus decreasing CREB-mediated transcription. In human cell culture, FAD-associated mutant PSEN1 inhibited this activity, and the mutant proteins were unable to suppress CREB-mediated transcription. Marambaud et al. (2003) suggested that FAD-associated PSEN1 mutations may lead to a gain of transcriptional function or at least transcriptional 'dysregulation.'
Teo et al. (2005) demonstrated that introduction of the PSEN1 mutant L286V (104311.0004) protein into rat neural precursor cells inhibited neurite outgrowth and neuronal differentiation by causing an increase in beta-catenin-mediated signaling and transcription. Molecular inhibition of beta-catenin/CBP-mediated transcription corrected these defects. Teo et al. (2005) also found that L286V mutant cells contained high levels of full-length N-cadherin and essentially no processed N-cadherin, reflecting a decrease in PSEN1-mediated epsilon-cleavage, as reported by Marambaud et al. (2003). Decreased processed N-cadherin was associated with increased levels of CBP, but not increased levels of p300 (602700), a similar protein that is part of the transcriptional complex. The findings suggested that CBP and p300 play unique and distinct roles in gene regulation. Teo et al. (2005) concluded that defective N-cadherin processing in the PSEN1 mutant cells led to increased beta-catenin/CBP-dependent transcription at the expense of beta-catenin/p300-mediated transcription, with a resultant block in neuronal differentiation. Within a broader context, Teo et al. (2005) suggested that this increased transcription may decrease the rate at which neuronal precursor cells differentiate into neurons in AD brains, which may exacerbate the decline in neural plasticity in the disease.
Other Functions
Kamal et al. (2000) demonstrated that the axonal transport of APP in neurons is mediated by the direct binding of APP to the kinesin light chain (600025) subunit of kinesin-I. Kamal et al. (2001) identified an axonal membrane compartment that contains APP, beta-secretase (604252), and presenilin-1. The fast anterograde axonal transport of this compartment is mediated by APP and kinesin-I. Proteolytic processing of APP can occur in the compartment in vitro and in vivo in axons. This proteolysis generates amyloid-beta and a carboxy-terminal fragment of APP, and liberates kinesin-I from the membrane. Kamal et al. (2001) concluded that APP functions as a kinesin-I membrane receptor, mediating the axonal transport of beta-secretase and presenilin-1, and that processing of APP to amyloid-beta by secretases can occur in an axonal membrane compartment transported by kinesin-I.
ERBB4 (600543) is a transmembrane receptor tyrosine that regulates cell proliferation and differentiation. After binding its ligand heregulin (142445) or activation of protein kinase C (see 176960) by TPA, the ERBB4-ectodomain is cleaved by a metalloprotease. Ni et al. (2001) reported a subsequent cleavage by gamma-secretase that releases the ERBB4 intracellular domain from the membrane and facilitates its translocation to the nucleus. Gamma-secretase cleavage was prevented by chemical inhibitors or a dominant-negative presenilin. Inhibition of gamma-secretase also prevented growth inhibition by heregulin. Ni et al. (2001) concluded that gamma-secretase cleavage of ERBB4 may represent another mechanism for receptor tyrosine kinase-mediated signaling.
Using binding assays with recombinant proteins, Nielsen et al. (2002) determined that PS1 interacts with a splice variant of glial fibrillary acidic protein (GFAP; 137780), which they called GFAP-epsilon. This variant contains a unique C terminus which is required for interaction with PS1. The originally identified GFAP protein, which they called GFAP-alpha, did not interact with PS1. By introducing point mutations in PS1 followed by yeast 2-hybrid analysis, they found that 2 nonconservative amino acid substitutions abolished interaction with GFAP-epsilon, but 2 conservative substitutions, both associated with Alzheimer disease, did not effect GFAP-epsilon binding. By transfection in human embryonic kidney cells and in mouse neuroblastoma cells, Nielsen et al. (2002) found that, while most GFAP-epsilon localized to filamentous structures, a subpopulation colocalized with PS1 in the perinuclear region and in cytoplasmic granules.
Katayama et al. (2001) and Yasuda et al. (2002) determined that FAD-linked mutations in PSEN1 disturb the unfolded protein response (UPR) which is activated in response to endoplasmic reticulum (ER) stress caused by the accumulation of misfolded proteins in the lumen of the ER. Cell culture studies showed that PSEN1 mutants inhibited activation of ER stress transducers Ire1-alpha (604033), ATF6 (605537), and PERK (604032). This leads to attenuation of the induction of the ER chaperone GRP78/BiP (138120) and inhibition of the translation-suppressing molecules eIF2-alpha (603907) and PERK. The authors concluded that this complex perturbation of the UPR leads to further accumulation of proteins in the ER, subsequently increasing vulnerability to ER stress. The FAD-linked PSEN1 mutations thus appear to result in a gain of function.
Tu et al. (2006) showed that recombinant presenilins, but not PSEN1 with the M146V mutation or PSEN2 with the N141I mutation, formed low-conductance cation-permeable channels in planar lipid bilayers following expression in insect cells. Embryonic fibroblasts from mice lacking both Psen1 and Psen2 had Ca(2+) signaling defects due to leakage from the ER, and the deficient calcium signaling in these cells could be rescued by expression of wildtype PSEN1 or PSEN2, but not by expression of PSEN1 with the M146V mutation or PSEN2 with the N141I mutation. The ER Ca(2+) leak function of presenilins was independent of their gamma-secretase activities. Tu et al. (2006) proposed that presenilins have a Ca(2+) signaling function, supporting the connection between deranged neuronal Ca(2+) signaling and Alzheimer disease.
Landman et al. (2006) demonstrated that dysregulation of the TRPM7 (605692)-associated Mg(2+)-inhibited cation channel underlies ion channel dysfunction in PSEN1 FAD-mutant cells. The channel deficits were restored by the addition of phosphatidylinositol 4,5-bisphosphate (PIP2), suggesting that an imbalance in PIP2 metabolism may be a factor in disease pathogenesis.
Using a yeast 2-hybrid assay with a human brain cDNA library, Pastorcic and Das (2007) found that the ETS transcription factor ERM (ETV5; 601600) bound full-length ZNF237 (ZMYM5; 616443). Both full-length ZNF237 and a truncated isoform repressed expression of a PS1 reporter when expressed in a human neuroblastoma cell line. Deletion analysis suggested that the N-terminal region of ZNF237 was required for interaction with ERM and for translational repression. EMSA revealed formation of a high molecular mass DNA-protein complex between the PS1 promoter region and in vitro-translated ZNF237 and ERM.
Zhang et al. (2009) used a genetic approach to inactivate presenilins conditionally in either presynaptic (CA3) or postsynaptic (CA1) neurons of the hippocampal Schaeffer-collateral pathway. They showed that long-term potentiation induced by theta-burst stimulation is decreased after presynaptic but not postsynaptic deletion of presenilins. Moreover, they found that presynaptic but not postsynaptic inactivation of presenilins alters short-term plasticity and synaptic facilitation. The probability of evoked glutamate release, measured with the open-channel NMDA (N-methyl-D-aspartate) receptor antagonist MK-801, is reduced by presynaptic inactivation of presenilins. Notably, depletion of endoplasmic reticulum Ca(2+) stores by thapsigargin, or blockade of Ca(2+) release from these stores by ryanodine receptor (see RYR3, 180903) inhibitors, mimics and occludes the effects of presynaptic presenilin inactivation. Zhang et al. (2009) concluded that, collectively, their results indicated a selective role for presenilins in the activity-dependent regulation of neurotransmitter release and long-term potentiation induction by modulation of intracellular Ca(2+) release in presynaptic terminals, and further suggested that presynaptic dysfunction might be an early pathogenic event leading to dementia and neurodegeneration in Alzheimer disease.
Cryoelectron Microscopy
The gamma-secretase complex, comprising presenilin, PEN2 (PSENEN; 607632), APH1AL (see 607629), and nicastrin (APH2; 605254), is a membrane-embedded protease that controls a number of important cellular functions through substrate cleavage. Lu et al. (2014) reported the 3-dimensional structure of an intact human gamma-secretase complex at 4.5-angstrom resolution, determined by cryoelectron microscopy single-particle analysis. The gamma-secretase complex comprises a horseshoe-shaped transmembrane domain, which contains 19 transmembrane segments and a large extracellular domain from nicastrin, which sits immediately above the hollow space formed by the transmembrane horseshoe. The nicastrin extracellular domain is structurally similar to a large family of peptidases exemplified by the glutamate carboxypeptidase PSMA.
Bai et al. (2015) reported an atomic structure of human gamma-secretase at 3.4-angstrom resolution, determined by single-particle cryoelectron microscopy. Mutations derived from Alzheimer disease affect residues at 2 hotspots in PS1, each located at the center of a distinct 4-transmembrane segment bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the transmembrane horseshoe, suggesting considerable conformational changes in the nicastrin extracellular domain after substrate recruitment. Component protein APH1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PSEN1. Ordered phospholipids stabilize the complex inside the membrane. Bai et al. (2015) suggested that their structure serves as a molecular basis for mechanistic understanding of gamma-secretase function.
Yang et al. (2019) reported the cryoelectron microscopy structure of human gamma-secretase in complex with a Notch (190198) fragment at a resolution of 2.7 angstroms. The transmembrane helix of Notch is surrounded by 3 transmembrane domains of PS1, and the carboxyl-terminal beta-strand of the Notch fragment forms a beta-sheet with 2 substrate-induced beta-strands of PS1 on the intracellular side. Formation of the hybrid beta-sheet is essential for substrate cleavage, which occurs at the carboxyl-terminal end of the Notch transmembrane helix. PS1 undergoes pronounced conformational rearrangement upon substrate binding. Yang et al. (2019) concluded that these features reveal the structural basis of Notch recognition and have implications for the recruitment of the amyloid precursor protein by gamma-secretase.
Zhou et al. (2019) reported the atomic structure of human gamma-secretase in complex with a transmembrane APP (104760) fragment at 2.6-angstrom resolution. The transmembrane helix of APP closely interacts with 5 surrounding transmembrane domains of PS1 (the catalytic subunit of gamma-secretase). A hybrid beta sheet, which is formed by a beta strand from APP and 2 beta strands from PS1, guides gamma-secretase to the scissile peptide bond of APP between its transmembrane and beta strand. Residues at the interface between PS1 and APP are heavily targeted by recurring mutations from Alzheimer disease patients.
Alzheimer Disease
Sherrington et al. (1995) identified 5 different missense mutations in the PSEN1 gene that cosegregated with early-onset familial Alzheimer disease type 3 (104311.0001-104311.0005). Because these changes occurred in conserved domains of this gene and were not present in normal controls, they were considered to be causative of disease.
Analyzing 40 families multiply affected by early-onset AD (under 60 years of age), in none of which any of the published mutations had been found, the Alzheimer's Disease Collaborative Group (1995) found 6 novel missense mutations in 13 families. None of these mutations occurred in either elderly unaffected individuals from the families concerned, control samples, or individuals with late-onset disease. The fact that no nonsense mutations were identified suggested that PS1 mutations cause alteration rather than loss of function of this protein. There was evidence that some of the mutations caused earlier onset ages than others. For example, 3 families with the M146V (104311.0007) mutation had onset ages between 36 and 40 years, whereas families with the C410Y (104311.0005) and E280A (104311.0009) mutations had mean onset ages between 45 and 50 years. All 11 of the known mutations altered residues that were conserved in the mouse homologs of PS1 and PS2. Of these mutations, 2 occurred at each of the codons 146, 163, and 280. Furthermore, the M146V mutation had occurred, apparently independently, in 3 pedigrees with different ethnic backgrounds. There also appeared to be a clustering of mutations in transmembrane domain 2. Predictions of protein secondary structure for the presenilins indicated to the authors that the proteins may have between 6 and 9 transmembrane domains; for this reason, the proposed gene name 'seven transmembrane protein' (STM) seemed unwise. Wasco et al. (1995) added 2 more novel PS1 mutations, bringing the total to 13.
Sherrington et al. (1995) pointed out that the AD3 locus is associated with the most aggressive form of Alzheimer disease, suggesting that mutations at the locus affect a biologically fundamental process. Clark et al. (1996) and St. George-Hyslop et al. (1996) reviewed the role of PS1 and PS2 in familial early-onset Alzheimer disease. Clark et al. (1996) tabulated mutations in the 2 genes, most of them in the PS1 gene.
In a systematic mutation analysis of all coding and 5-prime-noncoding exons of PS1 and PS2 in a population-based epidemiologic series of 101 unrelated familial and sporadic presenile AD cases, Cruts et al. (1998) identified 4 different PS1 missense mutations in 6 familial cases, 2 of which were autosomal dominant. Three new mutations resulted in onset ages above 55 years, with 1 segregating in an autosomal dominant family with mean onset age of 64 years. One PS2 mutation was identified in a sporadic case with onset age of 62 years. The data provided estimates for PS1 and PS2 mutation frequencies in presenile AD of 6% and 1%, respectively. In all 101 patients in this study, mutations in the amyloid precursor protein gene had previously been excluded. When family history was accounted for, mutation frequencies for PS1 were 9% in familial cases and 18% in autosomal dominant cases. Further, polymorphisms were detected in the promoter and the 5-prime noncoding region of PS1 and in intronic and exonic sequences of PS2 that will be useful in genetic association studies.
Gustafson et al. (1998) presented a 50-year history of a family with Alzheimer disease linked to chromosome 14. The authors found 6 cases of Alzheimer disease in 4 consecutive generations. All 6 affected cases demonstrated the typical neurologic signs and symptoms of Alzheimer disease. Cognitive decline began between 35 and 49 years of age. Mutation analysis of the PSEN1 gene on chromosome 14 demonstrated a met146-to-ile substitution (104311.0001).
Cruts and Van Broeckhoven (1998) counted 43 mutations that had been identified in the PS1 gene that led to familial presenile AD (onset before age 65 years). By contrast, only 3 mutations had been identified in PS2. Poorkaj et al. (1998) identified 3 novel PS1 mutations in early-onset AD. One of these mutations, ala426 to pro (104311.0014), was the most C-terminal PS1 mutation that had been identified.
Dermaut et al. (1999) stated that 49 different mutations in the coding region of the PSEN1 gene had been identified, making it the most frequently mutated gene in early-onset (onset age less than 65 years) Alzheimer disease. A glu318-to-gly (E318G) substitution was identified in the PSEN1 gene by several workers in familial AD cases with onset ages of 35 to 64 years. In an extensive study, Dermaut et al. (1999) came to the conclusion, however, that the E318G change was not causally related to either AD or other types of dementia. They found the mutation in heterozygous state in 4.1% of controls. They granted that it could not be excluded that the mutation was associated with dementia in homozygous state; however, there was no evidence supporting autosomal recessive inheritance in familial AD. Goldman et al. (2005) reported 2 unrelated patients with presenile dementia who carried the E318G change. However, genetic analysis of family members of the first patient showed that an unaffected family member carried the change and 1 affected member did not. Goldman et al. (2005) concluded that the E318G change is a polymorphism with uncertain clinical significance.
Among 414 patients, 372 with AD and 42 asymptomatic persons with a strong family history of AD, Rogaeva et al. (2001) identified 36 unique mutations, including 21 novel mutations, in the PSEN1 gene in 48 patients (11%). As 90% of those with PSEN1 mutations were affected by age 60 years, Rogaeva et al. (2001) concluded that PSEN1 screening in early-onset AD would likely be successful.
Theuns et al. (2000) systematically screened 3.5 kb of the PSEN1 upstream region and found 4 novel polymorphisms. Genetic analysis confirmed association of 2 of these polymorphisms with increased risk for early-onset AD. In addition, they detected 2 different mutations in early-onset AD cases, a -280C-G transversion and a -2818A-G transition, the positions of which were numbered relative to the transcription initiation site in exon 1A of PSEN1. Analysis of the mutant and wildtype -280 variants using luciferase reporter gene expression in transiently transfected neuroblastoma cells showed a 30% decrease in transcriptional activity for the mutant -280G PSEN1 promoter variant compared with the wildtype -280C variant. The data suggested that the increased risk for early-onset AD associated with PSEN1 may result from genetic variations in the regulatory region leading to altered expression levels of the PSEN1 protein.
Lambert et al. (2001) studied 287 individuals with Alzheimer disease. In addition, brain samples from a further 99 cases were studied. They carried out genotype analysis at the polymorphic site at position -48 in the PS1 gene promoter. Lambert et al. (2001) found an increased risk of developing Alzheimer disease associated with the -48CC genotype (odds ratio = 1.55; 95% CI 1.03 to 2.35). This appeared to be present in both familial and sporadic cases and independent of the APOE4 (see 107741) allele genotype. They also found that the A-beta load in the brains of individuals with the -48CC genotype was significantly increased (p less than 0.003).
Theuns et al. (2003) characterized the PSEN1 promoter by deletion mapping, and analyzed the effect of the -22C and -22T (also known as -48C/T based on a different numbering system) alleles on the transcriptional activity of PSEN1 in a transient transfection system. A neuron-specific 2-fold decrease in promoter activity for the -22C risk allele was observed, which in homozygous individuals may lead to a critical decrease in PSEN1 expression. The deletion mapping suggested that the 13-bp region (-33/-20) spanning the -22C-T polymorphism may harbor a binding site for a negative regulatory factor. Theuns et al. (2003) suggested that this factor may have a higher affinity for the -22C risk allele and may be strongly dependent on downstream sequences for cell type-specific expression differences.
In affected members of 24 of 31 families with early-onset AD, Raux et al. (2005) identified mutations in the PSEN1 gene. The mean age of disease onset was 41.7 years. Combined with earlier studies, the authors estimated that 66% of families with early-onset AD are attributable to mutations in the PSEN1 gene.
Using a photoaffinity probe approach, Chau et al. (2012) found that the M146L (104311.0001), E280A, and H163R (104311.0002) mutations in the PSEN1 gene influenced the shape of the S2 subsite of the gamma-secretase active site. The probe used showed about 80% less labeling of these mutant residues compared to wildtype. In vitro cellular studies showed that the mutant proteins had decreased gamma-secretase activity for cleavage of NOTCH1 (60-86% less active compared to wildtype), resulting from a decrease in Vmax.
Dilated Cardiomyopathy
Li et al. (2006) hypothesized that, since presenilins are expressed in the heart and are critical to cardiac development, mutations in presenilin may also be associated with dilated cardiomyopathy (CMD1U; 613694). They evaluated a total of 315 index patients with dilated cardiomyopathy for sequence variation in PSEN1 and PSEN2 (600759). A novel heterozygous PSEN1 missense mutation (104311.0034) was identified in 1 family, and a single heterozygous PSEN2 missense mutation (600759.0008) was found in 2 other families. The PSEN1 mutation was associated with complete penetrance and progressive disease that resulted in the necessity of cardiac transplantation or in death. Calcium signaling was altered in cultured skin fibroblasts from PSEN1 and PSEN2 mutation carriers.
Familial Acne Inversa
Wang et al. (2010) identified a family segregating autosomal dominant acne inversa-3 (ACNINV3; 613737) that was caused by a single-basepair frameshift mutation in PSEN1 (104311.0038). Wang et al. (2010) showed that heterozygous loss-of-function mutations in gamma-secretase components PSEN1, PSENEN (607632), and NCSTN (605254) can cause familial acne inversa. All known Alzheimer disease/dementia-causing PSEN mutations had been missense mutations or in-frame deletions or insertions. No affected individual studied by Wang et al. (2010) 50 years old or older had symptoms of Alzheimer disease or dementias.
To investigate the influence of the glu280-to-ala presenilin-1 gene mutation (E280A; 104311.0009) on regional cerebral perfusion, Johnson et al. (2001) used SPECT scanning in 57 individuals from 1 large pedigree with early-onset Alzheimer disease. The sample included 23 individuals who were not PS1 mutation carriers and were cognitively normal, 18 who were asymptomatic carriers, and 16 who were mutation carriers with a clinical diagnosis of AD. Asymptomatic subjects with PS1 mutations demonstrated reduced perfusion in comparison with the normal control subjects in the hippocampal complex, anterior and posterior cingulate, posterior parietal lobe, and anterior frontal lobe. The AD patients demonstrated decreased perfusion in the posterior parietal and superior frontal cortex in comparison with the normal control subjects. This method discriminated 86% of the subjects in the 3 groups (p less than 0.0005). Johnson et al. (2001) concluded that regional cerebral perfusion abnormalities based on SPECT are detectable before development of the clinical symptoms of Alzheimer disease in carriers of the glu280-to-ala PS1 mutation.
By genotype analysis of a large Colombian kindred with 109 carriers of the E280A PS1 mutation, including 52 members with AD, Pastor et al. (2003) found that those with at least 1 APOE4 allele were more likely to develop AD at an earlier age than those without an APOE4 allele, indicating an epistatic effect. Promoter APOE variants did not influence either the onset or the duration of the disease.
Ringman et al. (2005) reported that 51 nondemented carriers of FAD-linked PSEN1 mutations, ranging in age from 18 to 47 years, performed worse on neuropsychologic tests compared to noncarriers. The findings were consistent with early problems with memory, visuospatial function, and executive function in patients who eventually develop AD.
Moonis et al. (2005) found that 6 presymptomatic carriers of FAD-linked PSEN1 mutations, ranging in age from 34 to 55 years, had significantly lower CSF beta-amyloid-42 levels compared to 6 noncarriers. Although the authors stated that the mechanism for decline in CSF beta-amyloid is uncertain, it has been suggested that aggregation of beta-amyloid in the brain may leave less to circulate in the CSF; thus, decreased CSF levels may reflect a high concentration of brain amyloid plaque accumulation.
Highly sequence-similar presenilin homologs are known in plants, invertebrates and vertebrates. Ponting et al. (2002) searched various databases to identify a family of proteins homologous to presenilins. Members of this family, which they termed presenilin homologs, have significant sequence similarities to presenilins and also possess 2 conserved aspartic acid residues within adjacent predicted transmembrane segments. The presenilin homolog family was found throughout the eukaryotes, in fungi as well as plants and animals, and in archaea. Five presenilin homologs were detected in the human genome, of which 3 possess 'protease-associated' domains that are consistent with the proposed protease function of presenilins. Based on these findings, the authors proposed that presenilins and presenilin homologs represent different sub-branches of a larger family of polytopic membrane-associated aspartyl proteases.
Trower et al. (1996) used knowledge of the pufferfish (Fugu rubripes) genome to characterize the 14q24.3 region associated with autosomal dominant early-onset Alzheimer disease. Identification of genes in genomic regions associated with human diseases has been greatly facilitated by the development of techniques such as exon trapping (Buckler et al., 1991) and cDNA selection (Parimoo et al., 1991). Direct sequencing of disease loci has also been shown to be one of the most effective methods of gene detection, but it requires substantial sequencing capacity. The pufferfish (Fugu rubripes) genome is 7- to 8-fold smaller than that of the human (approximately 400 Mb compared to approximately 3,000 Mb), but it appears to contain a similar complement of genes. Thus, a typical cosmid clone of genomic DNA might be expected to contain 7 to 8 Fugu genes compared to only 1 human gene. Therefore, sequencing regions of the Fugu genome syntenic with a particular human disease region should accelerate the identification of candidate genes. Trower et al. (1996) demonstrated that 3 genes that are linked to FOS (164810) on 14q in the AD3 region have homologs in the Fugu genome adjacent to the Fugu FOS gene: dihydrolipoamide succinyltransferase (126063), S31iii125, and S20i15. In Fugu these 3 genes lie within a 12.4-kb region, compared to more than 600 kb in the human AD3 locus. The results demonstrated the conservation of synteny between the genomes of Fugu in man and highlighted the utility of this approach for sequence-based identification of genes in human disease genomic regions.
To understand the normal function of PS1, Shen et al. (1997) generated a targeted null mutation in the murine homolog of the gene. They found that homozygous PS1-deficient mice died shortly after natural birth or cesarean section. The skeleton of homozygous mutants was grossly deformed. Hemorrhages occurred in the CNS of PS1-null mutants with varying location, severity, and time of onset. The ventricular zone of homozygous deficient brains was strikingly thinner by embryonic day 14.5, indicating an impairment in neurogenesis. Bilateral cerebral cavitation caused by massive neuronal loss in specific subregions of the mutant brain was prominent after embryonic day 16.5. These results showed that PS1 is required for proper formation of the axial skeleton, normal neurogenesis, and neuronal survival. Davis et al. (1998) and Qian et al. (1998) generated mice deficient in PS1 and showed that the defects caused by the deficiency, described in detail by Shen et al. (1997), could be rescued by either wildtype human PS1 or by a human FAD-linked PS1 variant (A246E; 104311.0003), suggesting that even the mutant protein retains sufficient normal function in murine embryogenesis.
Donoviel et al. (1999) generated PS2-null mice by gene targeting, and subsequently, PS1/PS2 double-null mice. Mice homozygous for a targeted null mutation in PS2 exhibited no obvious defects; however, loss of PS2 on a PS1-null background led to embryonic lethality at embryonic day 9.5. Embryos lacking both presenilins, and surprisingly, those carrying only a single copy of PS2 on a PS1-null background, exhibited multiple early patterning defects, including lack of somite segmentation, disorganization of the trunk ventral neural tube, midbrain mesenchyme cell loss, anterior neuropore closure delays, and abnormal heart and second branchial arch development. In addition, Delta like-1 (176290) and Hes5, 2 genes that lie downstream in the Notch pathway, were misexpressed in presenilin double-null embryos. Hes5 expression was undetectable in these mice, whereas Delta like-1 was expressed ectopically in the neural tube and brain of double-null embryos. Donoviel et al. (1999) concluded that the presenilins play a widespread role in embryogenesis, that there is functional redundancy between PS1 and PS2, and that both vertebrate presenilins, like their invertebrate homologs, are essential for Notch signaling.
Wittenburg et al. (2000) demonstrated that in addition to its role in cell fate decisions in nonneuronal tissues, presenilin activity is required in terminally differentiated neurons in vivo. Mutations in the C. elegans presenilin genes sel-12 and hop-1 result in a defect in the temperature memory of the animals. This defect is caused by the loss of presenilin function in 2 cholinergic interneurons that display neurite morphology defects in presenilin mutants. The morphology and function of the affected neurons in sel-12 mutant animals can be restored by expressing sel-12 only in these cells. The wildtype human PS1, but not the familial Alzheimer disease (FAD) mutant PS1 A246E (104311.0003), can also rescue these morphologic defects. As lin-12 mutant animals display similar morphologic and functional defects to presenilin mutants, Wittenburg et al. (2000) suggested that presenilins mediate their activity in postmitotic neurons by facilitating Notch signaling. Wittenburg et al. (2000) concluded that their data indicates cell-autonomous and evolutionarily conserved control of neural morphology and function by presenilins.
Leissring et al. (2000) generated mutant PS1 knockin (KI) mice by replacing the endogenous mouse PS1 gene with human PS1 carrying the M146V mutation (104311.0007). In the KI mice, PS1 protein was expressed at physiologic levels and the endogenous tissue and cellular expression pattern was maintained. They found that agonist-evoked calcium signals were markedly potentiated in fibroblasts obtained from the KI mice. The KI cells also showed deficits in capacitative calcium entry, i.e., the influx of extracellular calcium triggered by depletion of intracellular calcium store. Both of these alterations were caused by an abnormal elevation of endoplasmic reticulum calcium stores.
Grilli et al. (2000) evaluated the relationship between PS1 and excitotoxicity in 4 different experimental models of neurotoxicity by using primary neurons from transgenic mice overexpressing a human FAD-linked PS1 variant, L286V (104311.0004); transgenic mice overexpressing human wildtype PS1; PS1 knockout mice; and wildtype mice in which PS1 expression was knocked down by antisense treatment. The results suggested that expression of FAD-linked PS1 variants increases the vulnerability of neurons to a specific type of damage in which excitotoxicity plays a relevant role. The data also supported the view that reduction of endogenous PS1 expression results in neuroprotection.
To determine if amyloid beta peptide vaccinations had deleterious or beneficial functional consequences, Morgan et al. (2000) tested 8 months of amyloid beta vaccination in transgenic models of Alzheimer disease in which mice develop learning deficits as amyloid accumulates. These models included the PS1 mutant, generated by Duff et al. (1996), and the APP mutant, generated by Hsiao et al. (1996), and a double transgenic that contained both mutations. Morgan et al. (2000) showed that vaccination with amyloid beta protected transgenic mice from the learning and age-related memory deficits that normally occur in this mouse model for Alzheimer disease. During testing for potential deleterious effects of the vaccine, all mice performed superbly on the radial-arm water-maze test of working memory. Later, at an age when untreated transgenic mice showed memory deficits, the amyloid-beta-vaccinated transgenic mice showed cognitive performance superior to that of the control transgenic mice and, ultimately, performed as well as nontransgenic mice. The amyloid beta-vaccinated mice also had a partial reduction in amyloid burden at the end of the study. Morgan et al. (2000) concluded that this therapeutic approach may thus prevent and possibly treat Alzheimer dementia.
Handler et al. (2000) analyzed Psen1-deficient mouse embryos and observed that lack of Psen1 leads to premature differentiation of neural progenitor cells. They concluded that Psen1 has a role in a cell fate decision between postmitotic neurons and neural progenitor cells. Handler et al. (2000) also detected changes in expression of genes involved in Notch signaling. They concluded that Psen1 controls neuronal differentiation in association with the downregulation of Notch signaling during neurogenesis.
Due to the perinatal lethality of Psen1 knockout mice, Yu et al. (2001) developed a conditional knockout mouse (cKO), in which Psen1 inactivation was restricted to the postnatal forebrain. The cKO mice were viable with no gross abnormalities, allowing Yu et al. (2001) to investigate the effects of Psen1 inactivation on amyloid precursor protein processing the Notch signaling pathway, and synaptic and cognitive function in the adult brain. They concluded from their studies that inactivation of Psen1 function in the adult cerebral cortex leads to reduced beta-amyloid generation and subtle cognitive deficits without affecting expression of Notch downstream target genes.
Feng et al. (2001) found that mice with selective deletion of the Psen1 gene in excitatory neurons of the forebrain showed deficient enrichment-induced neurogenesis in the hippocampal dentate gyrus. However, the mutant mice showed normal synaptic properties and learning comparable to wildtype. Feng et al. (2001) postulated that adult neurogenesis in the hippocampus may play a role in the periodic clearance of outdated hippocampal memory traces after cortical consolidation, thus allowing for new memory processing.
Using 3 groups of transgenic mice carrying the presenilin A246E mutation (104311.0003), the amyloid precursor protein K670N/M671L mutation (APP; 104760.0008), or both mutations, Dineley et al. (2002) showed that coexpression of both mutant transgenes resulted in accelerated beta-amyloid accumulation, first detected at 7 months in the cortex and hippocampus, compared to the APP or PS1 transgene alone. Contextual fear learning, a hippocampus-dependent associative learning task, but not cued fear learning, was impaired in mice carrying both mutations or the APP mutation, but not the PS1 mutation alone. The impairment manifested at 5 months of age, preceding detectable plaque deposition, and worsened with age. Dineley et al. (2002) also found increased levels of alpha-7 nicotinic acetylcholine receptor protein in the hippocampus, which they hypothesized contributes to disease progression via chronic activation of the ERK MAPK cascade.
Jankowsky et al. (2004) studied beta-amyloid-40 and -42 levels in a series of transgenic mice that coexpressed the APP 'Swedish' mutation (K670N/M671L) with 2 FAD-PS1 variants, A246E and the exon 9 deletion (104311.0012), that differentially accelerate amyloid pathology in the brain. There was a direct correlation between the concentration of beta-amyloid-42 and the rate of amyloid deposition. The shift in beta-amyloid-42:beta-amyloid-40 ratios associated with the expression of FAD-PS1 variants was due to a specific elevation in the steady-state levels of beta-amyloid-42, while maintaining a constant level of beta-amyloid-40. Jankowsky et al. (2004) suggested that PS1 variants may not simply alter the preferred cleavage site for gamma-secretase, but rather that they may have more complex effects on the regulation of gamma-secretase and its access to substrates.
Saura et al. (2004) generated a transgenic conditional double knockout mouse lacking both Psen1 and Psen2 in the postnatal forebrain. The mice showed impairments in hippocampal memory and synaptic plasticity at the age of 2 months, and later developed neurodegeneration of the cerebral cortex accompanied by increased levels of the Cdk5 activator p25 (603460) and hyperphosphorylated tau. The authors concluded that PSEN1 and PSEN2 have essential roles in synaptic plasticity, learning, and memory. Beglopoulos et al. (2004) found that double knockout mice lacking Psen1 and Psen2 in the postnatal forebrain had reduced levels of the toxic beta-amyloid peptides beta-40 and beta-42 and strong microglial activation in the cerebral cortex. Gene expression profiling showed an upregulation of genes associated with inflammatory responses. The results suggested that the memory deficits and neurodegeneration observed in the double knockout mice were not caused by beta-amyloid accumulation and implicated an inflammatory component to the neurodegenerative process.
Tournoy et al. (2004) reported that in PS1 +/- PS2 -/- mice, PS1 protein concentration was considerably lowered, functionally reflected by reduced gamma-secretase activity and impaired beta-catenin (CTNNB1; 116806) downregulation. Their phenotype was normal up to 6 months, when the majority of the mice developed an autoimmune disease characterized by dermatitis, glomerulonephritis, keratitis, and vasculitis, as seen in human systemic lupus erythematosus (152700). Besides B cell-dominated infiltrates, the authors observed a hypergammaglobulinemia with immune complex deposits in several tissues, high-titer nuclear autoantibodies, and an increased CD4+/CD8+ ratio. The mice further developed a benign skin hyperplasia similar to human seborrheic keratosis (182000) as opposed to malignant keratocarcinomata observed in skin-specific PS1 'full' knockouts.
Lazarov et al. (2005) found that exposure of transgenic mice coexpressing FAD-linked APP and PS1 variants to an enriched environment composed of large cages, running wheels, colored tunnels, toys, and chewable material resulted in pronounced reductions in cerebral beta-amyloid levels and amyloid deposits compared with animals raised under standard housing conditions. The enzymatic activity of a beta-amyloid-degrading endopeptidase, neprilysin (MME; 120520), was elevated in the brains of enriched mice and inversely correlated with amyloid burden. Moreover, DNA microarray analysis revealed selective upregulation in levels of transcripts encoded by genes associated with learning and memory, vasculogenesis, neurogenesis, cell survival pathways, beta-amyloid sequestration, and prostaglandin synthesis. These studies provided evidence that environmental enrichment leads to reductions in steady-state levels of cerebral beta-amyloid peptides and amyloid deposition and selective upregulation in levels of specific transcripts in brains of transgenic mice.
Guo et al. (2003) generated transgenic Drosophila in which the size of the eye was correlated with the level of endogenous gamma-secretase activity. The system was very sensitive to the levels of 3 genes required for APP gamma-secretase activity: presenilin, nicastrin (605254), and aph1 (see 607629). Using this system, the authors identified a region on the second chromosome that contains a gene or genes whose product(s) may promote gamma-secretase activity.
Esselens et al. (2004) found that cultured Ps1 -/- mouse hippocampal neurons showed increased amounts of Tln (ICAM5; 601852) protein and accumulation of Tln in phagocytic vacuoles distinct from classic autophagic vacuoles. Both the increased amount of Tln and Tln accumulation were independent of Ps1 gamma-secretase activity, since expression of dominant-negative human PS1 mutants in Ps1 -/- cells reversed both defects. Esselens et al. (2004) suggested that PS1 may have a role in targeting phagocytic vacuoles for lysosomal degradation.
Ganguly et al. (2008) showed that in Drosophila Ubqn (UBQLN1; 605046) binds to Psen1 and antagonizes Psen1 function in vivo. Loss of Ubqn suppressed phenotypes that resulted from loss of Psen1 function in vivo. Overexpression of Ubqn in the eye resulted in adult-onset, age-dependent retinal degeneration, which could be suppressed by Psen1 overexpression and enhanced by expression of a dominant-negative version of Psen1. Expression of a human AD-associated UBQLN1 variant led to more severe degeneration than expression of wildtype UBQLN1. The findings identified Ubqn as a regulator of Psen1, supported a role for UBQLN1 in AD pathogenesis, and suggested that expression of a human AD-associated variant can cause neurodegeneration independent of amyloid production.
Using morpholinos directed against splice acceptor sites in the zebrafish Psen1 transcript, Nornes et al. (2008) developed mutant zebrafish with aberrant splicing in the region between Psen1 exons 6 and 8. This mutation produced a truncated peptide with potent dominant-negative effect on Psen1 protein activity, including Notch signaling, and caused hydrocephaly. The effects of the mutation was independent of gamma-secretase, and did not disturb the formation or behavior of ventricular cilia.
Using an N-ethyl-N-nitrosourea mutagenesis screen, Bai et al. (2011) identified Columbus mutant mice, which exhibited motor axon midline crossing and a severe defect in ventral root formation. Bai et al. (2011) found that the Columbus mutation was a T-to-A transversion in intron 11 of the Psen1 gene that resulted in loss of Psen1 protein expression. Mouse embryos with targeted disruption of the Psen1 gene displayed a similar combination of pathfinding errors to those observed in Columbus mutants, including failure to form discrete ventral roots and midline crossing of motor axons. Motor neurons and commissural interneurons in Columbus mutants acquired an inappropriate attraction to floor plate netrin (see 601614) due to lack of gamma-secretase processing of the netrin signaling component Dcc (120470). Incomplete Dcc processing resulted in defective Slit (see 603742)/Robo (see 602430) silencing of netrin attractive signals and failure of commissural axons to exit the floor plate. Bai et al. (2011) concluded that PSEN1-mediated gamma-secretase activity is crucial to coordinate the attractive and repulsive signals that direct neural projections across the midline.
By screening a library of about 80,000 chemical compounds, Kounnas et al. (2010) identified a class of gamma-secretase modulators (GSMs), diarylaminothiazoles, or series A GSMs, that could target production of A-beta-42 and A-beta-40 in cell lines and in Tg 2576 transgenic AD mice. Immobilized series A GSMs bound to Pen2 and, to a lesser degree, Ps1. Series A GSMs reduced gamma-secretase activity without interfering with related off-target reactions, lowered A-beta-42 levels in both plasma and brain of Tg 2576 mice, and reduced plaque density and amyloid in Tg 2576 hippocampus and cortex. Daily dosing was well tolerated over the 7-month study.
Heneka et al. (2013) found that Nlrp3-null (606416) or Casp1-null (147678) mice carrying mutations associated with familial Alzheimer disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer disease, and demonstrated reduced brain caspase-1 and interleukin-1-beta (147720) activation as well as enhanced amyloid-beta clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-beta in the APP (104760)/PS1 model of Alzheimer disease. Heneka et al. (2013) concluded that their results showed an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer disease.
In 2 unrelated families with chromosome 14-linked early-onset Alzheimer disease (AD3; 607822), Sherrington et al. (1995) identified a mutation in the PSEN1 gene, resulting in a met146-to-leu (M146L) substitution. The authors detected the mutation in affected family members but not in asymptomatic family members aged more than 2 standard deviations beyond the mean age of onset and not on 284 chromosomes from unrelated, neurologically normal subjects drawn from comparable ethnic origins. The 2 families reported by Sherrington et al. (1995) were from southern Italy. Sorbi et al. (1995) studied 15 unrelated Italian families with necropsy-proven early-onset familial AD and found the met146-to-leu substitution in 3.
Morelli et al. (1998) described this mutation, due to an A-to-T transversion at the first position of codon 146, in an Argentinian family with early-onset FAD.
Halliday et al. (2005) identified the M146L substitution in 2 Australian sibs with early-onset FAD. Family history suggested that their father was also affected. Neuropathologic examination of both patients showed numerous cortical plaques and neurofibrillary tangles, consistent with AD. In addition, both cases showed ballooned neurons and numerous tau (MAPT; 157140)-immunoreactive Pick bodies in upper frontotemporal cortical layers and in the hippocampal dentate gyrus. Halliday et al. (2005) suggested that the M146L mutation may specifically predispose to both AD and Pick pathology by affecting multiple intracellular pathways involving tau phosphorylation.
Bruni et al. (2010) identified an AD3 family from Naples, Italy, with the M146L mutation. The 40-year-old proband showed memory loss with attention and planning deficits. Six other family members spanning 4 generations had developed dementia. Bruni et al. (2010) retrospectively identified 7 articles reporting AD3 families with the M146L mutation, including those reported by Sorbi et al. (1995) and Halliday et al. (2005). They also reviewed the Calabrian families reported by Sherrington et al. (1995). The reconstituted Calabrian families, the family from Naples, and the Australian family comprised 148 affected individuals, and a genealogic link from the 17th century was established for all the patients with the M146L mutation. The ancestral mutation originated from southern Italy. Phenotypic cluster analysis applied to 50 patients at onset and during the first 2 years identified 4 subgroups: 2 with a cognitive onset (58%), including memory loss or disorientation, and 2 with a behavioral onset (42%), including apathy, depression, and executive dysfunction. Neuropathologic examination of 2 patients showed substantial beta-amyloid and phosphorylated tau immunoreactivity throughout the cortex, deep brain regions, and brainstem, consistent with AD.
For 2 other mutations in the same codon, see met146-to-val (104311.0007) and met146-to-ile (104311.0015).
In an American pedigree with chromosome 14-linked Alzheimer disease (AD3; 607822), Sherrington et al. (1995) found a mutation in the PSEN1 gene, resulting in a his163-to-arg (H163R) substitution. The same mutation was found in a small French Canadian pedigree with early-onset Alzheimer disease.
In a pedigree with chromosome 14-linked early-onset Alzheimer disease (AD3; 607822), Sherrington et al. (1995) identified a mutation in the PSEN1 gene, resulting in an ala246-to-glu substitution (A246E).
In a pedigree with chromosome 14-linked early-onset Alzheimer disease (AD3; 607822), Sherrington et al. (1995) identified a mutation in the PSEN1 gene, resulting in a leu286-to-val (L286V) substitution.
In 2 pedigrees with early-onset Alzheimer disease (AD3; 607822), Sherrington et al. (1995) identified a mutation in the PSEN1 gene, resulting in a cys410-to-tyr (C410Y) substitution.
In 2 families with early-onset Alzheimer disease (AD3; 607822), the Alzheimer's Disease Collaborative Group (1995) detected a mutation in the PSEN1 gene, resulting in a met139-to-val (M139V) substitution. In both families, the mean age of onset was 39 to 41 years.
Hull et al. (1998) described a German family with early-onset Alzheimer disease caused by the M139V mutation. From the age of 43 years, the proband had complained of deficits in short-term memory. Relatives had noticed his symptoms even earlier and dated the onset of deficits to age 38 years when he showed increasing interruptions during speech followed by social withdrawal. There was a strong family history of dementia. Through 3 generations the onset of dementia in this family was between 42 and 45 years. Fox et al. (1997) reported on this mutation in a British family.
Rippon et al. (2003) reported an African American family with atypical early-onset AD caused by the M139V mutation.
In 3 unrelated early-onset Alzheimer disease families (AD3; 607822), the Alzheimer's Disease Collaborative Group (1995) found a met146-to-val (M146V) mutation in the PSEN1 gene. See also the M146L mutation (104311.0001). The age of onset was unusually early in these 3 families, between 36 and 40 years.
In a Swedish family in which 8 members had early-onset Alzheimer disease (AD3; 607822), the Alzheimer's Disease Collaborative Group (1995) identified an his163-to-tyr (H163Y) mutation. The average age of onset was 47 years. See also the H163R mutation (104311.0002).
In 4 families with onset of Alzheimer disease in their late forties (AD3; 607822), the Alzheimer's Disease Collaborative Group (1995) found a glu280-to-ala (E280A) mutation in the AD3 gene.
With this and other missense mutations in the PS1 gene, increased levels of amyloid beta-peptides ending at residue 42 are found in plasma and skin fibroblast media of gene carriers. A-beta-42 aggregates readily and appears to provide a nidus for the subsequent aggregations of A-beta-40, resulting in the formation of innumerable neuritic plaques. To obtain in vivo information about how PS1 mutations cause AD pathology at such early ages, Lemere et al. (1996) characterized the neuropathologic phenotype of 4 patients from a large Colombian kindred bearing the glu280-to-ala substitution in PS1. Using antibodies specific to the alternative C-termini of A-beta, they detected massive deposition of A-beta-42 (the earliest and predominant form of plaque A-beta to occur in AD) in many brain regions. Quantification revealed a significant increase in the A-beta-42 form, but not the A-beta-40 form, in the brains from 4 patients with the PS1 mutation compared with those from 12 sporadic AD patients. Thus, Lemere et al. (1996) concluded that the mutant PS1 protein appears to alter the proteolytic processing of the beta-amyloid precursor protein at the C-terminus of A-beta to favor deposition of A-beta-42.
Lopera et al. (1997) screened all members of 5 extended families (nearly 3,000 individuals) in a community based in Antioquia, Colombia, where early-onset Alzheimer disease due to the glu280-to-ala mutation had been shown to be unusually frequent. Using standard diagnostic criteria, a case series of 128 individuals was identified, of which 6 had definitive (autopsy-proven) early-onset AD, 93 had probable early-onset AD, and 29 had possible early-onset AD. The patients had a mean age at onset of 46.8 years (range, 34 to 62 years). The average interval until death was 8 years. Headache was noted in affected individuals significantly more frequently than in those not affected. The most frequent presentations were memory loss followed by behavioral and personality changes and progressive loss of language ability. In the final stages, gait disturbances, seizures, and myoclonus were frequent. Kosik et al. (2015) identified 6 homozygous carriers of the E280A mutation among the large cohort of extended families from Colombia reported by Lopera et al. (1997). Two of the individuals (age range 44-46 years old) had dementia for 1 to 7 years before the time of ascertainment (range of dementia onset 37 to 45 years). These individuals presented 5 and 13 years before the mean age at onset of dementia for the entire kindred. Five of the 6 homozygous individuals were female. The findings indicated that homozygosity for the E280A mutation exists and is not lethal, and may be associated with an accelerated age at dementia onset compared to heterozygous mutation carriers.
Johnson et al. (2001) demonstrated that regional cerebral perfusion abnormalities based on SPECT are detectable before development of the clinical symptoms of Alzheimer disease in carriers of the glu280-to-ala PS1 mutation.
By genotype analysis of a large Colombian kindred with 109 carriers of the E280A PS1 mutation, including 52 members with AD, Pastor et al. (2003) found that those with at least 1 APOE4 allele (see 107741) were more likely to develop AD at an earlier age than those without an APOE4 allele, indicating an epistatic effect. Promoter APOE variants did not influence either the onset or the duration of the disease.
In a woman from the very large Colombian family with early-onset Alzheimer disease caused by a heterozygous E280A mutation in the PSEN1 gene, who did not develop mild cognitive impairment until her seventies, Arboleda-Velasquez et al. (2019) detected homozygosity for an arginine-to-serine substitution at amino acid 136 (R136S) on the APOE3 allele of APOE (107741.0034). The R136S mutation in APOE is known as the Christchurch mutation, and the authors referred to the APOE allele in this individual as APOE3ch.
In 2 families with multiple cases of Alzheimer disease with onset in the early forties (AD3; 607822), the Alzheimer's Disease Collaborative Group (1995) found a glu280-to-gly (E280G) mutation in the AD3 gene. See also the E280A mutation (104311.0009).
In 1 of the families with the E280G mutation reported by the Alzheimer's Disease Collaborative Group (1995), O'Riordan et al. (2002) described an atypical disease pattern in 3 additional members from the third generation who developed symptoms in their forties (see 607822). One had cognitive impairment, spastic paraparesis, and white matter abnormalities on MRI. One of his sibs developed dementia and myoclonus and had white matter abnormalities on MRI. Another sib had ophthalmoplegia, spastic-ataxic quadriparesis, and cotton-wool plaques with amyloid angiopathy on brain biopsy (MRI was not performed). The authors suggested that the MRI findings may reflect an ischemic leukoencephalopathy due to amyloid angiopathy affecting meningocortical vessels.
In a patient with Alzheimer disease with spastic paraparesis and cotton-wool plaques with onset at age 52 years, Rogaeva et al. (2003) identified the E280G mutation, which they incorrectly reported as E280Q. Rogaeva (2004) reported the correct mutation as E280G. There were 4 other affected members in the patient's family.
In 1 family with early-onset Alzheimer disease (AD3; 607822) with a mean onset of 35 years, the Alzheimer's Disease Collaborative Group (1995) detected a pro267-to-ser (P267S) mutation in the AD3 gene.
Perez-Tur et al. (1995) found a heterozygous mutation changing G to T in the splice acceptor site for exon 9 in a family segregating Alzheimer disease with linkage to chromosome 14 (AD3; 607822). RT-PCR of cDNA isolated from lymphoblasts of affected members demonstrated an aberrant band in the sequence of which exon 9 was deleted in-frame, removing amino acids 290 to 319. The authors suggested that since the predicted protein structure would retain the same overall topology as the wildtype protein, exon 9 was of particular relevance to the abnormal physiology of presenilin 1 in Alzheimer disease.
Thinakaran et al. (1996) demonstrated that PS1 undergoes endoproteolytic processing in vivo to yield 27-kD N-terminal and 17-kD C-terminal derivatives, cleaved between amino acids 260 and 320. In a British FAD pedigree with the PS1 exon 9 deletion, there was no cleavage of PS1.
Crook et al. (1998) described the same deletion of exon 9 in a Finnish pedigree with 17 affected individuals of both sexes in 3 generations suffering from a novel variant of Alzheimer disease. The mechanism of the deletion of exon 9 in this family was not a mutation in the acceptor splice site, however, and remained to be determined. The disorder in the Finnish pedigree was characterized by progressive dementia that was in most cases preceded by spastic paraparesis (see 607822). Neuropathologic investigations showed numerous distinct, large, round, and eosinophilic plaques, as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton-wool balls and were immunoreactive for A-beta, but lacked a congophilic dense core or marked plaque-related neuritic pathology.
Crook et al. (1998) referred to this mutation as the delta-9 mutation. They stated that it was the only known structural mutation in the PSEN1 gene; previously identified mutations had been missense mutations. The delta-9 mutant protein is not metabolized to the stable 18-kD N-terminal and the 28-kD C-terminal fragments, and thus the mutant holoprotein accumulates. Unlike the missense mutations, the delta-9 mutation rescues the egl phenotype caused by mutations in sel-12, the C. elegans homolog of the presenilins. Of the mutations described in the PSEN1 gene, the delta-9 mutation has the greatest effect on A-beta-42(43) production.
The missense mutations in the PSEN1 gene give rise to phenotypic manifestations that differ very little from classic AD, apart from an unusually early onset. Kwok et al. (1997) reported another family with an association between a splice acceptor site mutation of PSEN1 (resulting in the delta-9 deletion) and presenile AD with spastic paraparesis. Kwok et al. (1997) reported a second family in which an arg278-to-thr missense mutation (104311.0017) was associated with presenile AD and spastic paraparesis. In a fourth case, reported by Kwok et al. (1997), the mutation was not identified. As summarized by Crook et al. (1998), spastic paraparesis had been reported in 2 of 4 families with the delta-9 mutation and in 2 other families. Thus, the association of this syndrome with the delta-9 mutation is not a simple one.
In this variant form of Alzheimer disease, spastic paraparesis precedes dementia and large A-beta-amyloid plaques resembling cotton-wool balls are a leading neuropathologic feature. The disorder has been described in a Finnish pedigree (Verkkoniemi et al., 2000; Crook et al., 1998) and in an Australian pedigree (Smith et al., 2001). In the family of Smith et al. (2001), the onset of dementia was delayed and modified in subjects with spastic paraparesis. This phenotypic variation suggested that modifying factors are associated with exon 9 deletions.
Reznik-Wolf et al. (1996) used denaturing gradient gel electrophoresis to examine the PS1 gene in several Israeli families with early-onset Alzheimer disease (AD3; 607822). They found that 2 siblings with early-onset AD carried a missense mutation changing codon 120 from glutamic acid to aspartic acid. This allele was not found in 118 control individuals.
In a Scottish-Irish family with early-onset Alzheimer disease (AD3; 607822), Poorkaj et al. (1998) identified an A-to-C change at nucleotide 1278 in the PSEN1 gene that resulted in an ala426-to-pro (A426P) substitution.
In a Danish family with autosomal dominant early-onset Alzheimer disease (AD3; 607822) spanning 3 generations, Jorgensen et al. (1996) identified a G-A transition in the PSEN1 gene, resulting in a met146-to-ile (M146I) substitution. The average age of disease onset was 44 years.
In a Swedish family with Alzheimer disease in 4 consecutive generations, Gustafson et al. (1998) identified a single base substitution (ATG to ATC) in codon 146 of the PSEN1 gene, resulting in an M146I substitution.
Harvey et al. (1998) described a family in which 7 members had early-onset Alzheimer disease (AD3; 607822) due to a leu250-to-ser (L250S) missense mutation in the PSEN1 gene. Detailed clinical information was available on 5 members. All had an early age at onset, with a median age of 52 years. Age at onset varied between 49 and 56 years, with duration of illness varying between 6 years and 15 years. Myoclonus, depression, and psychosis were features in this family; seizures were not reported.
Kwok et al. (1997) described an arg278-to-thr mutation of the PSEN1 gene associated with Alzheimer disease with spastic paraparesis and distinctive large eosinophilic plaques (see 607822), as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton-wool balls and were immunoreactive for A-beta, but lacked a congophilic dense core or marked plaque-related neuritic pathology. This pathologic change was seen in 2 families with deletion of exon 9 of the PSEN1 gene (104311.0012).
In 2 autopsy-confirmed cases with early-onset Alzheimer disease (AD3; 607822), Tysoe et al. (1998) identified a single-base deletion of a G at the splice donor site of intron 4 of the PSEN1 gene. De Jonghe et al. (1999) identified the same mutation in 4 additional, unrelated early-onset AD cases and demonstrated that the mutation segregates in an autosomal dominant manner and that all cases have 1 common ancestor. De Jonghe et al. (1999) showed that the intron 4 mutation produces 3 different transcripts, 2 deletion transcripts (1 involving a deletion of all of exon 4 and the other involving a deletion of part of exon 4), and a transcript that results in insertion of a threonine between codons 113 and 114. The truncated proteins were not detectable in vivo in brain homogenates or in lymphoblast lysates of mutation carriers. In vitro, HEK293 cells overexpressing the insertion cDNA construct or either of the deletion constructs showed amyloid beta-42 secretion approximately 3 to 4 times greater than normal only for the insertion cDNA construct. Increased amyloid beta-42 production was also observed in brain homogenates. De Jonghe et al. (1999) concluded that in the case of the intron 4 mutation, the Alzheimer disease pathophysiology results from increased amyloid beta-42 secretion by the insertion transcript, comparable with cases carrying a dominant PSEN1 missense mutation.
Devi et al. (2000) studied 2 children who developed dementia in their late twenties (AD3; 607822). Their father had early-onset, autopsy-confirmed Alzheimer disease. The younger of the 2 children had AD confirmed at autopsy. Sequencing of the coding region of the PSEN1 gene revealed a GC-to-TG substitution at nucleotides 1548-1549, affecting codon 434. There was no DNA source available on their father for mutation analysis. The disease course in these 3 individuals was characterized by cognitive and behavioral problems accompanied by myoclonus, seizures, and aphasia within 5 years after onset.
Lewis et al. (2000) showed that cys92-to-ser (C92S), the PS1 homolog of the C. elegans sel-12 loss of function mutation cys60 to ser, increased amyloid beta-42 production when expressed in a neuroglioma cell line, similar to other pathogenic PS1 mutations. They noted, but did not cite, a report identifying C92S as the pathogenic mutation in an Italian family with familial Alzheimer disease (AD3; 607822). The results suggested that all FAD-linked PS1 mutations result in increased amyloid beta-42 production through a partial loss of function mechanism.
Athan et al. (2001) found that among 206 Caribbean Hispanic families with 2 or more living members with AD, 19 (9.2%) had at least 1 individual with onset of Alzheimer disease before the age of 55 years (AD3; 607822). In 8 of these 19 families, a gly206-to-ala mutation in the PSEN1 gene was identified. Although not known to be related, all carriers of the G206A mutation tested shared a variant allele at 2 nearby microsatellite polymorphisms, indicating a common ancestor.
In a Japanese family with 6 individuals of both genders in 2 generations affected by a variant form of Alzheimer disease characterized by senile dementia preceded by spastic paraparesis and apraxia (see 607822), Matsubara-Tsutsui et al. (2002) identified a G-to-A transition in codon 266 of exon 8 of the PSEN1 gene, resulting in a gly-to-ser (G266S) substitution. The deceased patients were between 48 and 51 years of age.
Raux et al. (2000) reported 6 members of a family with early-onset frontotemporal dementia (see 600274), confirmed by imaging studies, in an autosomal dominant inheritance pattern. In 2 patients available for testing, the authors found a novel heterozygous T-to-A mutation in the PSEN1 gene, resulting in a leu113-to-pro substitution. The mutation was absent in a healthy sister and in 50 unrelated patients. Raux et al. (2000) noted that this phenotype is usually associated with mutation in the MAPT gene (157140).
Moehlmann et al. (2002) identified a leu166-to-pro (L166P) mutation in the PSEN1 gene in a female proband in whom the onset of familial Alzheimer disease was in adolescence (AD3; 607822). Generalized seizures began at age 15, major depression occurred at age 19, memory was clearly impaired by 24, ataxia and spastic paraplegia were recorded by 27, and moderate stage dementia by 28. Dementia, ataxia, and spasticity progressed until death at age 35. Numerous A-beta-immunopositive neuritic and cotton-wool plaques were seen throughout the cerebral cortex and A-beta-immunopositive amyloid cores were abundant in the cerebellar cortex. This was stated to be 1 of 11 mutations associated with FAD and located in the third transmembrane domain (TM3) of PSEN1. An analysis of other FAD-associated and artificial L166 mutants showed increased A-beta(42) levels in all, suggesting that leucine-166 is critically required for the specificity of gamma-secretase cleavage. However, none of the L166 mutations inhibited gamma-secretase activity.
Bertoli Avella et al. (2002) studied a Cuban family with autosomal dominant presenile Alzheimer disease (AD3; 607822) through 6 generations that descended from a Spanish founder who migrated from the Canary Islands in the early 19th century. Mean age at onset was 59 years. Memory impairment was the main symptom in all patients; ischemic episodes were described in 4. Neuropathologic examination of brain material in 1 patient revealed neuronal loss, amyloid plaques, and neurofibrillary tangles. A maximum lod score of 3.79 at theta = 0.0 was obtained for marker D14S43, located in a 9-cM interval of the PSEN1 gene in which all patients shared the same haplotype. Sequencing of the PSEN1 gene revealed a heterozygous 520C-A substitution in exon 6, which was predicted to cause a leu174-to-met (L174M) substitution in the third transmembrane domain of the protein. Leu174 is highly conserved among species and is identical in presenilin-1 and presenilin-2 proteins.
In a family with autosomal dominant early-onset Alzheimer disease (see 607822), Kwok et al. (2003) identified a C-T mutation in the PSEN1 gene, resulting in a leu271-to-val (L271V) substitution and deletion of exon 8. Mean age of disease onset was 49 years, and although no affected family members had spastic paraparesis, all developed myoclonus late in the illness. Neuropathologic examination of 2 patients revealed a large number of neocortical large spherical plaques without defined cores or neuritic dystrophy, reminiscent of cotton wool plaques. Biochemical analysis of the mutated protein showed that it resulted in increased secretion of the amyloid-beta-42 peptide.
In a patient with Pick disease (172700), Dermaut et al. (2004) identified a G-to-T transversion in exon 6 of the PSEN1 gene, resulting in a gly183-to-val (G183V) substitution. The mutation occurs at a conserved residue within a splice signal. The mutation was not detected in more than 1,000 patients with dementia and normal controls. Four sibs of the proband had the mutation; 1 was clearly affected and 3 others showed evidence compatible with cognitive deterioration or early-stage cognitive decline. Neuropathologic examination of the proband showed tau (MAPT; 157140)-immunoreactive Pick bodies without beta-amyloid plaques. Dermaut et al. (2004) suggested that the G183V mutation results in a partial loss of function of the PSEN1 protein.
Beck et al. (2004) reported a patient with sporadic early-onset Alzheimer disease (AD3; 607822) who was a somatic mosaic for a 71111C-A transversion in exon 12 of the PSEN1 gene. The mutation, which had been described by Taddei et al. (1998), was predicted to result in substitution of glutamine at proline-436 (P436Q). The index patient presented at age 52 years with a 10-year history of progressive parkinsonian syndrome, spastic paraparesis, and dementia; she died 6 years later. The degree of mosaicism was 8% in peripheral lymphocytes and 14% in the cerebral cortex of the index patient. Her daughter, who presented at age 27 years with progressive cerebellar syndrome, spastic paraparesis, and dementia, was heterozygous for the mutation; she died 12 years after diagnosis. The authors hypothesized that mosaicism may be an important mechanism in the etiology of sporadic AD and other apparently sporadic neurodegenerative diseases such as Parkinson disease (see 168601), motor neuron disease, and Creutzfeldt-Jakob disease (123400).
In 2 sibs with early-onset Alzheimer disease with spastic paraparesis and unusual plaques (see 607822), Moretti et al. (2004) identified a heterozygous 6-bp insertion (715insTTATAT) in exon 3 of the PSEN1 gene, resulting in the addition of phenylalanine and isoleucine between codons 156 and 157. The affected region encodes the intracellular loop between transmembrane domains 2 and 3 of PSEN1 and is highly conserved. The patients showed an unusually aggressive form of disease, with early onset and rapid progression.
In 2 sibs with early-onset Alzheimer disease (AD3; 607822) presenting as language impairment, Godbolt et al. (2004) identified a heterozygous mutation in the PSEN1 gene, resulting in an arg278-to-ile (R278I) substitution. Both patients presented at around age 50 with difficulty in word finding and impaired frontal executive function, but with relative preservation of memory. Although neither patient fulfilled clinical consensus criteria for AD, the authors noted that a different mutation at the same codon, R278T (104311.0017), had been associated with an atypical AD phenotype characterized by spastic paraparesis. Codon 278 lies in the cytoplasmic region between transmembrane regions 6 and 7 which is active in the formation of the gamma-secretase complex that mediates beta-amyloid generation (Takasugi et al., 2003).
In a patient with very-early-onset Alzheimer disease with spastic paraparesis and apraxia (see 607822), Ataka et al. (2004) identified a heterozygous 254T-C transition in exon 4 of the PSEN1 gene, resulting in a leu85-to-pro (L85P) substitution. Functional expression studies showed that the L85P mutation resulted in a 2-fold increase in amyloid-beta-42 production. The patient had onset at age 26 years, and symptoms and neuroimaging were consistent with the 'visual variant' of AD in which there is a visuospatial cognitive deficit.
In a Japanese patient with a phenotype with overlapping features of early-onset Alzheimer disease with spastic paraparesis and unusual plaques (see 607822) and Lewy body dementia (DLB; 127750), Ishikawa et al. (2005) identified a 3-bp deletion (ACC) in exon 12 of the PSEN1 gene, resulting in the absence of residue thr440 at the cytoplasmic C-terminus of the protein. The patient's father had early-onset dementia with the onset of parkinsonism 9 years later, consistent with Lewy body dementia. However, the patient had early-onset parkinsonism with the onset of dementia 7 years later, and developed seizures and features of spasticity late in the illness. Neuropathologic examination of the patient showed severe neuronal loss with gliosis in various brain regions, as well as alpha-synuclein (SNCA; 163890)-immunopositive Lewy bodies, amyloid (APP; 104760)-immunopositive cotton-wool plaques, cerebral amyloid angiopathy, and corticospinal degeneration. The patient's clinical diagnosis was Parkinson disease with dementia, and the pathologic diagnosis was AD with spastic paraparesis. No mutations were identified in the SNCA or APP genes. Ishikawa et al. (2005) emphasized the unusual phenotypic features in this patient. The thr440 deletion induced both alpha-synuclein and beta-amyloid pathology to equal extents, suggesting that normal PSEN1 protein may play a role in interactions between the 2 molecules.
In affected members of 9 Mexican families with early-onset Alzheimer disease-3 (AD3; 607822), Yescas et al. (2006) identified a heterozygous mutation in exon 12 of the PSEN1 gene, resulting in an ala431-to-glu (A431E) substitution. The A431E mutation was found in 19 (32%) of 60 apparently unaffected family members, suggesting either a presymptomatic state or reduced penetrance. All families were from the state of Jalisco in western Mexico, and haplotype analysis indicated a founder effect. The A431E mutation was not identified in 100 control individuals.
Murrell et al. (2006) found the A431E mutation in 20 individuals with AD3 from 15 families identified in Guadalajara, southern California, and Chicago. Age at disease onset ranged from 33 to 44 years, and spasticity was a common clinical feature. Fourteen families were of Mexican mestizo descent, and of these families, 9 could trace the illness to ancestors from the state of Jalisco in Mexico. The remaining proband had a more remote Mexican ancestry. The findings further supported a founder effect for the A431E mutation.
Li et al. (2006) described heterozygosity for a novel PSEN1 missense mutation, asp333 to gly (D333G), associated with dilated cardiomyopathy (CMD1U; 613694) in 1 African American family. The amino acid substitution arose from a 1539A-G transition in exon 10. Affected members were identified in 3 generations. The PSEN1 mutation was associated with complete penetrance and progressive disease that resulted in the necessity of cardiac transplantation or in death.
In 3 affected members of a family with Alzheimer disease (AD3; 607822), Kauwe et al. (2007) identified a heterozygous C-to-T transition in exon 4 of the PSEN1 gene, resulting in an ala79-to-val (A79V) substitution. The patients had late-onset AD (greater than 75 years) that was confirmed at autopsy. An unaffected mutation carrier in the family was found to have increased CSF beta-amyloid-42, suggesting that this may be used as an endophenotype or marker for the disease. In vitro functional expression studies in mouse embryonic fibroblasts transfected with the A79V mutation showed increased beta-amyloid-42 compared to controls.
In 3 affected members of a family with early-onset Alzheimer disease (AD3; 607822), Snider et al. (2005) identified a heterozygous C-to-T transition in exon 6 of the PSEN1 gene, resulting in a ser170-to-phe (S170F) substitution. All 3 patients developed gradual onset of memory loss beginning at 26 to 27 years of age, with an average duration of disease of 11 years before death. The clinical courses were complicated by myoclonus, seizures, and extrapyramidal signs. Postmortem examination confirmed AD in all 3 patients. The proband also had widespread Lewy body pathology in the brainstem, limbic system, and neocortex; specific staining for Lewy bodies was not performed in the other 2 family members.
In a man with early-onset AD associated with cerebellar ataxia, Piccini et al. (2007) identified a heterozygous S170F mutation in the PSEN1 gene, which was not identified in 94 control individuals. The patient presented at age 28 years with delusions and lower limb jerks accompanied by intentional myoclonus and cerebellar ataxia. He had rapid progression with global impairment of all cognitive functions and became bedridden, anarthric, and incontinent by age 33. He died of bronchopneumonia at age 35. Postmortem examination showed severe beta-amyloid deposition in the cerebral and cerebellar cortices, amyloid angiopathy, and severe loss of Purkinje cells and fibers in the cerebellum. Neurofibrillary tangles were also present in the cerebral cortex. In vitro cellular studies indicated that the S170F mutation resulted in a 2.8-fold increase of both beta-amyloid-42 and -40 as well as a 60% increase of secreted APP compared to wildtype PSEN1. Soluble and insoluble fractions of the patient's brain tissue showed a prevalence of N-terminally truncated beta-amyloid species at residues 40 and 42. Piccini et al. (2007) suggested that the unique processing pattern of APP and high levels of N-terminally truncated species was correlated with the severity of the phenotype in this patient, but also noted the different phenotype from that described by Snider et al. (2005).
In 2 affected members of a family of Irish/English descent with Alzheimer disease with unusual cotton wool plaques (see 607822), Norton et al. (2009) identified a heterozygous G-to-C transversion in the PSEN1 gene, resulting in a gly217-to-arg (G217R) substitution. There were 8 affected family members. The mean age at onset was 45.5 years, and the mean age at death was 55.5 years. Postmortem examination of 1 affected family member showed classic Alzheimer disease changes and large cotton wool plaques. Spastic paraparesis was not a clinical feature. In vitro functional expression assays showed that the G217R mutation increased the ratio of beta-amyloid 42/40, confirming its pathogenicity.
In a Han Chinese family segregating autosomal dominant familial acne inversa (ACNINV3; 613737), Wang et al. (2010) identified heterozygosity for a single-basepair deletion at nucleotide 725 of the PSEN1 gene (725delC). The mutation resulted in frameshift and a premature termination codon (Pro242LeufsTer11). No affected individual 50 years old or older had symptoms of Alzheimer disease or dementia. This mutation was not identified in chromosomes from 200 ethnically matched control individuals.
In 3 brothers with early-onset Alzheimer disease with spastic paraparesis (see 607822) and unusually rapid progression, Dolzhanskaya et al. (2014) identified a heterozygous c.1141C-T transition in the PSEN1 gene, resulting in a leu381-to-phe (L381F) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database and segregated with the disorder in the family. The boys' father and paternal grandmother were reportedly similarly affected. The brothers had onset of progressive dementia and ataxia between ages 29 and 32 years; 2 died by age 32 and the other at age 36. The proband presented with memory deficits and ataxia, and later developed dysarthria, and spastic paraparesis. Electron microscopy of a skin biopsy showed lipofuscin-containing phagocytic cells and distinct curvilinear lysosomal inclusion bodies, suggestive of neuronal ceroid lipofuscinosis. Neuropathologic examination showed changes consistent with Alzheimer disease, including neuritic and amyloid-containing plaques and neurofibrillary tangles. Additional findings included Hirano bodies and granulovacuolar degeneration in the hippocampus. The proband was originally ascertained from a cohort of patients clinically thought to have autosomal dominant adult-onset neuronal ceroid lipofuscinosis (CLN4B; 162350) who were negative for mutations in the DNAJC5 gene (611203). Functional studies of the L381F variant were not performed.
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