Alternative titles; symbols
HGNC Approved Gene Symbol: LAMP2
SNOMEDCT: 419097006; ICD10CM: E74.05;
Cytogenetic location: Xq24 Genomic coordinates (GRCh38): X:120,426,148-120,469,349 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq24 | Danon disease | 300257 | X-linked dominant | 3 |
The lysosomal membrane plays a vital role in the function of lysosomes by sequestering numerous acid hydrolases that are responsible for the degradation of foreign materials and for specialized autolytic functions. LAMP1 (153330) and LAMP2 are glycoproteins that constitute a significant fraction of the total lysosomal membrane glycoproteins. Both consist of polypeptides of about 40 kD, with 16 to 20 N-linked saccharides attached to the core polypeptides (Fukuda et al., 1988).
Fukuda et al. (1988) isolated human cDNAs encoding LAMP1 and LAMP2.
Using mouse Lgp110 to screen a human liver cDNA library, Konecki et al. (1994) cloned LAMP2. Sequencing analysis indicated that there are 4 polyadenylation signals in the 3-prime UTR, with the second being the most frequently used. The deduced 410-amino acid protein contains a leader sequence; a luminal domain consisting of 2 homologous domains with 4 identically spaced cysteines linked by 2 disulfide bonds; a 20-amino acid transmembrane region; and a short cytoplasmic tail containing the lysosomal membrane targeting signal. The protein is heavily N-glycosylated.
By screening human liver and pheochromocytoma cDNA libraries, Konecki et al. (1995) identified a LAMP2 variant, which they called LAMP2B, that results from alternative splicing of exon 9. They designated the variant reported by Konecki et al. (1994) as LAMP2A. The deduced LAMP2B protein contains 410 amino acids, like the LAMP2A protein, but its C-terminal sequence differs in the last 11 amino acids of the luminal domain, the transmembrane domain, and the cytoplasmic tail. LAMP2B retains the lysosomal targeting signal, gly-tyr-x-x, and has the same number of potential glycosylation sites as LAMB2A. The LAMP2B variant has 3 polyadenylation signals in the 3-prime UTR. Using a common 5-prime LAMP2 sequence as probe for Northern blot analysis, Konecki et al. (1995) identified 6 major LAMP2 transcripts in liver and 4 major transcripts in pheochromocytoma mRNA. By Northern blot analysis using LAMP2B-specific probes, they detected highest expression of LAMP2B in skeletal muscle, with very low expression in liver. LAMP2B was also expressed in fibroblasts and fetal liver. Northern blot analysis using LAMP2A-specific probes detected highest LAMP2A expression in placenta, lung, and liver, with much lower expression in skeletal muscle. Immunoelectron microscopy localized LAMP2 primarily on the luminal side of endocytic organelles. No labeling of the plasma membrane was observed.
LAMP2 is thought to protect the lysosomal membrane from proteolytic enzymes within lysosomes and to act as a receptor for proteins to be imported into lysosomes (Fukuda, 1994).
Kain et al. (2008) found that virtually all individuals with pauci-immune focal necrotizing glomerulonephritis (FNGN) had autoantibodies against LAMP2 and that autoantibodies against LAMP2 caused this disease when injected into rats. A monoclonal antibody to human LAMP2 induced apoptosis of human microvascular endothelium in vitro. The autoantibodies in individuals with pauci-immune FNGN commonly recognize a human LAMP2 epitope with 100% homology to the bacterial adhesin FimH, with which they crossreact. Rats immunized with FimH developed pauci-immune FNGN and also developed antibodies to rat and human LAMP2. Finally, Kain et al. (2008) showed that infections with fimbriated pathogens are common before the onset of FNGN. Thus, Kain et al. (2008) concluded that FimH-triggered autoimmunity to LAMP2 provides a previously undescribed clinically relevant molecular mechanism for the development of pauci-immune FNGN.
Konecki et al. (1995) determined that the LAMP2 gene contains 9 coding exons, with 2 alternate last exons, 9a and 9b.
By in situ hybridization, Mattei et al. (1990) mapped the LAMP2 gene to Xq24-q25. This was taken to support the view that LAMP1 and LAMP2 diverged relatively early in evolution and that they have distinct functions which emerged as soon as eukaryotic cells acquired lysosomes as subcellular compartments.
Isolation and identification of human genes can be helped by isolation of cDNA clones, identification of DNA fragments conserved in distant species, and direct sequence analysis. Identification of CpG islands is an additional tool. CpG islands, unmethylated tracts of DNA that are 0.5 to 2 kb long and very rich in G+C and in the dinucleotide CpG, are located in the 5-prime region of all sequenced housekeeping genes and of many tissue-specific genes (Bird, 1987). The lack of methylation of CpG islands makes them a preferential site of cleavage for methylation-sensitive restriction enzymes with one or more CpGs in their recognition site, such as HpaII, EagI, SacII, BssHII, and NotI. Lindsay and Bird (1987) demonstrated the usefulness of CpG islands as landmarks for identifying genes. In an EagI-EcoRI library of the distal long arm of the human X chromosome, Manoni et al. (1991) found a clone that mapped to Xq24 (by hybridization with a panel of human-hamster cell hybrids carrying deletions of different portions of the human X chromosome between Xq24 and Xqter). Using Southern hybridization and hamster/human hybrid cell panels, Schleutker et al. (1991) confirmed the localization of the LAMP2 gene on the X chromosome. In the course of high-resolution comparative mapping of the proximal region of the mouse X chromosome, Blair et al. (1995) demonstrated the location of the Lamp2 gene in relation to others.
In 10 patients with Danon disease (300257), Nishino et al. (2000) identified mutations in the LAMP2 gene (see, e.g., 309060.0001-309060.0006).
Charron et al. (2004) analyzed the LAMP2 gene in 50 patients diagnosed with hypertrophic cardiomyopathy (CMH; see 192600) who were negative for mutations in 9 sarcomeric genes and did not have autosomal dominant inheritance. The authors identified 2 different mutations in the LAMP2 gene (309060.0008 and 309060.0009)in 2 patients, both of whom had skeletal muscle weakness on examination and PAS-positive sarcoplasmic vacuoles on skeletal muscle biopsy by light microscopy.
LAMP2 mutations typically cause multisystem Danon disease, which can also present as a primary cardiomyopathy. In genetic analyses of 24 subjects with increased left ventricular wall thickness and electrocardiogram suggesting ventricular preexcitation, Arad et al. (2005) found 4 LAMP2 mutations (see, e.g., 309060.0010) and 7 PRKAG2 (602743) mutations. Clinical features associated with defects in LAMP2 included male sex, severe hypertrophy, early onset (at 8 to 17 years of age), ventricular preexcitation, and asymptomatic elevations of 2 serum proteins. Mutations in heterozygous state appeared to be responsible for unusual heart disease in some females.
In a family (XLCM-2) that presented with dilated cardiomyopathy and was linked to the dystrophin gene (300377) by Towbin et al. (1993), Taylor et al. (2007) identified a mutation in the LAMP2 gene (309060.0012), confirming a diagnosis of Danon disease.
Roos et al. (2018) identified hemizygosity or heterozygosity for a splicing mutation in the LAMP2 gene (309060.0013) in 4 males and 3 females from a family with variable features of Danon disease. LAMP2 expression was decreased in fibroblasts from the proband.
Tanaka et al. (2000) generated mice deficient in Lamp2 by targeted disruption. Lamp2 knockout mice showed elevated mortality and reduced weight compared with their wildtype littermates. About 50% of Lamp2-deficient animals died between postnatal days 20 and 40, independent of sex and genetic background (C57B6/Jx129SV and 129SV). In addition, Lamp2-deficient mice were smaller than wildtype mice. Surviving mice were fertile and had an almost normal life span. Ultrastructurally, there was extensive accumulation of autophagic vacuoles in many tissues, including liver, pancreas, spleen, kidney, and skeletal and heart muscle. In hepatocytes, the autophagic degradation of long-lived proteins was severely impaired. Cardiac myocytes were ultrastructurally abnormal and heart contractility was severely reduced. These findings indicated that LAMP2 is critical for autophagy. This theory was further substantiated by the finding that human LAMP2 deficiency, which causes Danon disease, is associated with the accumulation of autophagic material in striated myocytes.
In a Japanese male (patient 1) with Danon disease (300257) diagnosed after muscle biopsy, Nishino et al. (2000) identified a 2-bp deletion (1097delAA) in exon 9b of the LAMP2 gene, resulting in a frameshift.
In a Japanese male (patient 2) with Danon disease (300257), Nishino et al. (2000) identified a 440T-A transversion in the LAMP2 gene, resulting in a leu113-to-ter (L113X) substitution.
In a Japanese male (patient 3) with Danon disease (300257), Nishino et al. (2000) identified a G-to-C transversion at the +5 position of intron 6 of the LAMP2 gene. This mutation resulted in the skipping of exon 6.
In an Italian male (patient 4) with Danon disease (300257), Nishino et al. (2000) identified a 1-bp insertion (974insA) in exon 8 of the LAMP2 gene, resulting in a frameshift. This patient was initially described by Dworzak et al. (1994).
In affected males from 3 different families with Danon disease (300257), Nishino et al. (2000) identified a 6-bp insertion at the junctions of exons 5 and 6 of the LAMP2 gene. The inserted nucleotides had the same sequence as the 5-prime end of intron 5. Conceivably, nucleotides 7 and 8 (GT) immediately after the inserted sequence in intron 5 were recognized as an alternative splice donor site. The inserted sequence encoded an in-frame stop codon, which predicted premature termination of the nascent polypeptide. This mutation was found in a Japanese family (patient 6), an African American family (patient 7), and an Anglo-Saxon family (patient 8). The African American family was originally reported by Danon et al. (1981), and the Anglo-Saxon family had been reported by Riggs et al. (1983).
In a male patient (patient 9) from a large Greek family with Danon disease (300257) initially reported by Byrne et al. (1986), Nishino et al. (2000) identified a 1-bp deletion (14delG) in exon 1 of the LAMP2 gene, resulting in a frameshift.
Takahashi et al. (2002) described a brother and sister with Danon disease (300257) who had 1-bp insertion (883insT) in the LAMP2 gene. The mutation was not detected in their mother's peripheral blood or buccal cells, thus indicating germline mosaicism. The proband was a 7-year-old boy with normal early motor and cognitive development, found to have an abnormal EKG and elevated blood creatinine kinase. EKG indicated left ventricular hypertrophy, confirmed by echocardiogram. Neurologic examination showed normal mentation and mild weakness of the neck muscles. He attended regular school. The 6-year-old sister had developed normally and had an unremarkable clinical examination, but on EKG showed left ventricular hypertrophy and by echocardiogram hypertrophic cardiomyopathy.
In a 24-year-old male with Danon disease (300257), Charron et al. (2004) identified a 7-bp deletion (173del7) in the LAMP2 gene, resulting in a frameshift and a premature stop at codon 17. The patient's mother also carried the mutation; 3 of her brothers and her mother had premature cardiac deaths at ages ranging from 7 to 34 years. The patient had markedly decreased left ventricular function with an ejection fraction of 20%, mild distal muscle weakness, mild amyotrophy of the lower limbs with pes cavus, and no mental retardation; he also had severe decreased visual acuity bilaterally, due to choriocapillary atrophy. He died of heart failure at 25 years of age while awaiting transplantation.
In a patient with Danon disease (300257), Charron et al. (2004) identified a de novo 657C-T transition in exon 4 of the LAMP2 gene, resulting in a gln174-to-ter (Q174X) substitution. The patient was diagnosed at age 14 years because of syncope, at which time ECG revealed normal sinus rhythm with high QRS voltage and Wolff-Parkinson-White syndrome and echocardiography showed increased left ventricular wall thickness with no outflow tract gradient and a normal ejection fraction. He had mild skeletal weakness but no mental retardation or ophthalmic abnormality. At 22 years of age, he underwent cardiac transplantation due to severe heart failure and died in the postoperative period.
In a male proband with Danon disease (300257), described as glycogen storage disease presenting as hypertrophic cardiomyopathy, Arad et al. (2005) found a 928G-A transition in the LAMP2 gene that resulted in a val310-to-ile (V310I) amino acid substitution. The mutation affected RNA processing and hence produced a frameshift (K289FS). Genetic studies demonstrated mosaicism: both mutant and wildtype LAMP2 sequences were identified despite a normal XY karyotype.
In a male patient with hypertrophic cardiomyopathy, exercise intolerance, and hyperCKemia consistent with a mild form of Danon disease (300257), Musumeci et al. (2005) identified a 961T-C transition in exon 8 of the LAMP2 gene, resulting in a trp321-to-arg (W321R) substitution in a highly conserved region of the protein. Muscle biopsy showed LAMP2 deficiency, PAS-positive sarcoplasmic vacuoles, and intense staining for complement C5b-9 membrane attack complex proteins within the vacuoles. The patient did not have muscle weakness or mental retardation. Musumeci et al. (2005) stated that this was the first missense mutation reported in the LAMP2 gene.
In affected members of a family with Danon disease (300257), originally studied by Towbin et al. (1993), Taylor et al. (2007) identified a 1-bp deletion (1219delA) in exon 8 of the LAMP2 gene, resulting in a frameshift at codon 361 predicted to obliterate the carboxy sequences for both the lysosomal transmembrane and lysosomal targeting domains. The mutation was present in all affected individuals and obligate carriers tested, and was not found in over 300 control chromosomes. The patients had dilated and hypertrophic cardiomyopathy, cardiac preexcitation, and skeletal myopathy with elevated CK levels.
In 4 males and 3 females from a family with variable features of Danon disease (300257), Roos et al. (2018) identified hemizygosity or heterozygosity for a splicing mutation in the LAMP2 gene. Skipping of exon 6 was confirmed by sequencing of LAMP2 cDNA in fibroblasts from the proband. LAMP2 expression was decreased in patient fibroblasts.
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