Alternative titles; symbols
HGNC Approved Gene Symbol: MME
SNOMEDCT: 1187128001, 1208516002;
Cytogenetic location: 3q25.2 Genomic coordinates (GRCh38): 3:155,024,202-155,183,729 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q25.2 | ?Spinocerebellar ataxia 43 | 617018 | Autosomal dominant | 3 |
| Charcot-Marie-Tooth disease, axonal, type 2T | 617017 | Autosomal dominant; Autosomal recessive | 3 |
The MME gene encodes a widely expressed membrane metalloendopeptidase that degrades a number of substrates. The active site of the enzyme faces the extracellular space (summary by Higuchi et al., 2016).
Common acute lymphocytic leukemia antigen (CALLA) is an important cell surface marker in the diagnosis of human acute lymphocytic leukemia (ALL). It is present on leukemic cells of pre-B phenotype, which represent 85% of cases of ALL. CALLA is not restricted to leukemic cells, however, and is found on a variety of normal tissues. CALLA is a glycoprotein that is particularly abundant in kidney, where it is present on the brush border of proximal tubules and on glomerular epithelium. Letarte et al. (1988) cloned a cDNA coding for CALLA and showed that the amino acid sequence deduced from the cDNA sequence is identical to that of human membrane-associated neutral endopeptidase (NEP; EC 3.4.24.11), also known as enkephalinase. NEP cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin.
Barker et al. (1989) determined that the CALLA gene encodes a 100-kD type II transmembrane glycoprotein.
Higuchi et al. (2016) found expression of the MME gene in the myelin sheath of a human sural nerve, with lesser expression in the axon.
By cDNA transfection analysis, Shipp et al. (1989) confirmed that CALLA is a functional neutral endopeptidase of the type that has previously been called enkephalinase.
CALLA has also been called atriopeptidase. Atriopeptidase specifically degrades atrial natriuretic factor (ANF; 108780) (Stephenson and Kenny, 1987; Koehn et al., 1987). Northridge et al. (1989) developed a specific enzyme inhibitor and reported that it had effects similar to those of low-dose ANF infusion. These effects include diuresis, natriuresis, vasodilatation, and suppression of the renin-angiotensin-aldosterone system.
Debiec et al. (2002) described a case in which anti-neutral endopeptidase antibodies produced by a pregnant woman were transferred to a fetus, in which a severe form of membranous glomerulonephritis (614692) developed prenatally. The mother had a deficiency of neutral endopeptidase and probably had become immunized against the antigen at the time of or after an earlier miscarriage. This was the first podocytic antigen that had been found to be involved in human membranous glomerulonephritis. Despite the absence of neutral endopeptidase, the mother was healthy, as were mice with a targeted disruption of the neutral endopeptidase gene, suggesting enzymatic redundancy.
To determine whether decreased neprilysin levels contribute to the accumulation of amyloid (104760) deposits in Alzheimer disease (AD; 104300) or normal aging, Russo et al. (2005) analyzed MME mRNA and protein levels in cerebral cortex from 10 cognitively normal elderly individuals with amyloid plaques (NA), 10 individuals with AD, and 10 controls who were free of amyloid plaques. They found a significant decrease in MME mRNA levels in both AD and NA individuals compared to controls. Russo et al. (2005) concluded that decreased MME expression correlates with amyloid-beta deposition but not with degeneration and dementia.
Wisner et al. (2006) showed that opiorphin, an analgesic pentapeptide originating from PROL1 (608936), was a physiologic inhibitor of neutral ecto-endopeptidase and ecto-aminopeptidase N (ANPEP; 151530).
Barker et al. (1989) demonstrated that the CALLA gene exists in a single copy of greater than 45 kb that is not rearranged in malignancies expressing cell surface CALLA.
D'Adamio et al. (1989) demonstrated that the CALLA gene spans more than 80 kb and is composed of 24 exons.
Barker et al. (1989) localized the CALLA gene to human chromosome 3 by study of somatic cell hybrids and regionalized the location to 3q21-q27 by in situ hybridization. Tran-Paterson et al. (1989) also assigned the gene to chromosome 3 by Southern blot analysis of DNA from human-rodent somatic cell hybrids.
Charcot-Marie-Tooth Disease Type 2T
In 10 Japanese probands with autosomal recessive Charcot-Marie-Tooth disease type 2T (CMT2T; 617017), Higuchi et al. (2016) identified homozygous or compound heterozygous mutations in the MME gene (see, e.g., 120520.0001-120520.0005). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families in whom segregation was analyzed. All but 1 of the mutations resulted in a splice site defect or a truncated protein, consistent with a loss-of-function mechanism. MME mutations accounted for 13% of patients with a diagnosis of autosomal recessive CMT who underwent whole-exome sequencing, and Higuchi et al. (2016) concluded that mutations in the MME gene are the most frequent cause of autosomal recessive axonal CMT in the Japanese population.
In 19 probands of European descent with late-onset autosomal dominant axonal CMT (see 617017), Auer-Grumbach et al. (2016) identified 11 different heterozygous variants in the MME gene (see, e.g., 120520.0007-120520.0009), including 7 loss-of-function alleles and 4 missense alleles. The variants in the first 3 families were found by whole-exome sequencing; subsequent MME variants were found in 6 of 45 additional probands with a similar disorder who underwent direct sequencing of the MME gene. Select patient samples and in vitro cellular studies were consistent with decreased tissue availability of neprilysin and impaired enzymatic activity. Examination of repositories of whole-exome data from more than 10,000 individuals with neurologic and other disorders found 12 more individuals with heterozygous truncating variants, 10 of whom had polyneuropathy, motor neuron disorder, or sensory ataxia. Statistical analysis showed that MME loss-of-function variants were overrepresented among cases with late-onset CMT2T compared to controls in several large databases; however, some of the variants were also present in controls and sometimes showed incomplete penetrance in family studies, suggesting that heterozygous variants may confer susceptibility to the late-onset axonal CMT.
Spinocerebellar Ataxia 43
In 7 affected members of a large Belgian family with spinocerebellar ataxia-43 (SCA43; 617018), Depondt et al. (2016) identified a heterozygous missense mutation in the MME gene (C143Y; 120520.0006). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. Sequencing of the MME gene in 96 additional patients with dominant ataxia did not identify any more mutations.
Amyloid-beta peptide, the pathogenic agent of Alzheimer disease, is a physiologic metabolite in the brain. Iwata et al. (2001) examined the role of neprilysin, a candidate amyloid-beta degrading peptidase, in the metabolism using neprilysin gene-disrupted mice. Neprilysin deficiency resulted in defects both in the degradation of exogenously administered amyloid-beta and in the metabolic suppression of the endogenous amyloid-beta levels in a gene dose-dependent manner. The regional levels of amyloid-beta in the neprilysin-deficient mouse brain were in the distinct order of hippocampus, cortex, thalamus/striatum, and cerebellum, where hippocampus has the highest level and cerebellum the lowest, correlating with the vulnerability to amyloid-beta deposition in brains of humans with Alzheimer disease. Iwata et al. (2001) concluded that even partial downregulation of neprilysin activity, which could be caused by aging, can contribute to Alzheimer disease by promoting amyloid-beta accumulation.
Leissring et al. (2003) found that developmentally delayed, neuron-specific overexpression of Ide (146680) or neprilysin in mice significantly reduced brain beta-amyloid levels, retarded or prevented amyloid plaque formation and its associated cytopathology, and rescued the premature lethality in APP transgenic mice. They concluded that chronic upregulation of beta-amyloid-degrading proteases may combat Alzheimer-type pathology in vivo.
Saito et al. (2005) found that somatostatin (SST; 182450) modulated the proteolytic degradation of beta-amyloid catalyzed by neprilysin both in vitro and in vivo. Primary cortical neurons treated with somatostatin showed an upregulation of neprilysin activity and a reduction in A-beta-42. Sst-null mice showed a 1.5-fold increase in hippocampal A-beta-42, but not A-beta-40. Saito et al. (2005) noted that expression of somatostatin in the brain declines with normal aging, and postulated that a similar decrease in neprilysin activity with gradual accumulation of toxic beta-amyloid may underlie late-onset AD.
In animal cell culture studies, Pardossi-Piquard et al. (2005) found that endogenous gamma-secretase-dependent AICD fragments from APP-like proteins, including APP, APLP1 (104775) and APLP2 (104776), induced transcriptional activation of neprilysin by binding to its promoter. Neprilysin, in turn, was partly responsible for the degradation of beta-amyloid-40. Psen1 (104311)/Psen2 (600759)-deficient mouse fibroblasts or blastocysts were unable to efficiently degrade beta-amyloid-40 due to decreased neprilysin activity and protein expression. Single Psen1-deficient or Psen2-deficient cells had normal levels of neprilysin protein and activity, indicating that depletion of both Psen genes was necessary to affect transcription of neprilysin. The findings provided evidence for a regulatory mechanism in which varying levels of gamma-secretase activity modulate beta-amyloid degradation via AICD fragments. Chen and Selkoe (2007) questioned the findings of Pardossi-Piquard et al. (2005) and provided their own experimental evidence that neprilysin levels and/or activity were not affected by lack of APP, Psen1/Psen2 genotypes, or inhibition of gamma-secretase. In response, Pardossi-Piquard et al. (2007) defended their original findings and provided further evidence that Psen complexes and AICD modulate neprilysin expression in some cells.
Auer-Grumbach et al. (2016) found that homozygous Mme-null mice were overtly normal in appearance and size and did not show obvious abnormalities in motor performance or coordination. Nerve conduction studies revealed no significant differences between mutant and control animals. However, histologic and electron microscopic studies showed some axonal abnormalities: the myelinated fibers appeared more densely packed with smaller extracellular spaces, and there were some abnormally shaped bundles of unmyelinated fibers.
In affected individuals from 3 unrelated Japanese families (families 1, 2, and 3) with autosomal recessive Charcot-Marie-Tooth disease type 2T (CMT2T; 617017), Higuchi et al. (2016) identified a homozygous G-to-A transition in intron 7 (c.654+1G-A) of the MME gene, resulting in the skipping of exon 7, a frameshift, and premature termination (Gly179AspfsTer2). The mutation, which was found by whole-exome sequencing, was not found in the dbSNP (build 137), 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in a large in-house database of over 4,000 controls. The mutation segregated with the disorder in 1 of the families; segregation analysis was not performed on the other 2 families. Haplotype analysis showed that 2 of the 3 families shared a region containing the mutation.
In a patient (P5), born of consanguineous Japanese parents, with autosomal recessive Charcot-Marie-Tooth disease type 2T (CMT2T; 617017), Higuchi et al. (2016) identified a homozygous c.661C-T transition in exon 8 of the MME gene, resulting in a gln221-to-ter (Q221X) substitution. There were 3 other similarly affected family members, but segregation analysis was not performed. The mutation, which was found by whole-exome sequencing, was not found in the dbSNP (build 137), 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in a large in-house database of over 4,000 controls. Patient cells showed no mutant mRNA, suggesting nonsense-mediated decay.
In 2 brothers, born of consanguineous Japanese parents (family 4), with autosomal recessive Charcot-Marie-Tooth disease type 2T (CMT2T; 617017), Higuchi et al. (2016) identified a homozygous c.1861T-C transition in exon 19 of the MME gene, resulting in a cys621-to-arg (C621R) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing, was not found in the dbSNP (build 137), 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in a large in-house database of over 4,000 controls. Sural nerve biopsy from 1 of the patients showed decreased amounts of MME compared to controls, consistent with a loss of function.
In a man (patient 7), born of consanguineous Japanese parents, with autosomal recessive Charcot-Marie-Tooth disease type 2T (CMT2T; 617017), Higuchi et al. (2016) identified a homozygous T-to-A transversion in intron 5 of the MME gene (c.439+2T-A), resulting in the skipping of exon 5 and an in-frame deletion of 27 residues (Asp120_Glu146del) from the catalytic domain. The mutation, which was found by whole-exome sequencing, was not found in the dbSNP (build 137), 1000 Genomes Project, the Exome Sequencing Project, or the ExAC databases, or in a large in-house database of over 4,000 controls. The mutation segregated with the disorder in the family. An unrelated Japanese patient (patient 8) with the disorder was compound heterozygous for the c.439+2T-A mutation and another splice site mutation (120520.0005).
In a Japanese man, born of consanguineous parents (family 10), with autosomal recessive Charcot-Marie-Tooth disease type 2T (CMT2T; 617017), Higuchi et al. (2016) identified a homozygous A-to-G transition (c.655-2A-G) in intron 7 the MME gene, resulting in the skipping of exon 8 and an in-frame deletion of 22 residues (Ile219_Glu240del) from the catalytic extracellular domain. The mutation, which was found by whole-exome sequencing, was not found in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases; it was found at very low frequency in the ExAC database and in a large in-house database of over 4,000 controls. The mutation segregated with the disorder in the family.
In 7 affected members of a large Belgian family with autosomal dominant spinocerebellar ataxia-43 (SCA43; 617018), Depondt et al. (2016) identified a heterozygous G-to-A transition in the MME gene, resulting in a cys143-to-tyr (C143Y) substitution at a highly conserved residue in the N-terminal peptidase M13 domain within a group of cysteines in the extracellular portion of the protein. This cysteine forms a disulfide bridge in the linker portion. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing. It segregated with the disorder in the family and was not present in the dbSNP, Exome Variant Server, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed. Sequencing of the MME gene in 96 additional patients with dominant ataxia did not identify any more mutations.
In 6 patients from 2 unrelated Austrian families (AT1 and AT2) with late-onset autosomal dominant Charcot-Marie-Tooth disease type 2T (see 617017), Auer-Grumbach et al. (2016) identified a heterozygous 1-bp deletion (c.466delC, NM_000902.3) in exon 5 of the MME gene, resulting in a frameshift and premature termination (Pro156LeufsTer14) in one of the peptidase domains. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Sanger sequencing of the MME gene in 45 additional individuals with a similar disorder identified 8 patients from 5 families with the same heterozygous mutation. Adipose tissue biopsies and plasma from the patients showed significantly lower concentrations of neprilysin compared to controls. The variant was also present in 5 of 6,251 individuals in the Exome Variant Server database and in 20 of 60,245 individuals in the ExAC database, as well as in several in-house databases (less than 0.03%).
In an Austrian woman (family AT3) with late-onset autosomal dominant Charcot-Marie-Tooth disease type 2T (see 617017), Auer-Grumbach et al. (2016) identified a heterozygous c.71G-A transition (c.71G-A, NM_000902.3) in exon 1 of the MME gene, resulting in a trp24-to-ter (W24X) substitution just before the transmembrane domain. The variant, which was found by whole-exome sequencing, was not found in the dbSNP (build 142), 1000 Genomes Project, Exome Variant Server, or ExAC databases. Patient adipose tissue and plasma showed significantly lower concentrations of neprilysin compared to controls.
In an Austrian mother and son (family AT8) with late-onset autosomal dominant Charcot-Marie-Tooth disease type 2T (see 617017), Auer-Grumbach et al. (2016) identified a heterozygous c.1265C-A transversion (c.1265C-A, NM_000902.3) in exon 12 of the MME gene, resulting in an ala422-to-asp (A422D) substitution at a highly conserved residue in one of the peptidase domains. Transfection of the mutation into HEK293 cells showed that the mutant protein had significantly decreased neprilysin activity, consistent with a loss of function and haploinsufficiency. The variant was found 4 times in the ExAC database.
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Debiec, H., Guigonis, V., Mougenot, B., Decobert, F., Haymann, J.-P., Bensman, A., Deschenes, G., Ronco, P. M. Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies. New Eng. J. Med. 346: 2053-2060, 2002. [PubMed: 12087141] [Full Text: https://doi.org/10.1056/NEJMoa012895]
Depondt, C., Donatello, S., Rai, M., Wang, F. c., Manto, M., Simonis, N., Pandolfo, M. MME mutation in dominant spinocerebellar ataxia with neuropathy (SCA43). Neurol. Genet. 2: e94, 2016. Note: Electronic Article. [PubMed: 27583304] [Full Text: https://doi.org/10.1212/NXG.0000000000000094]
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Koehn, J. A., Norman, J. A., Jones, B. N., LeSoeur, L., Sakane, Y., Ghai, R. D. Degradation of atrial natriuretic factor by kidney cortex membranes. J. Biol. Chem. 262: 11623-11627, 1987. [PubMed: 2957371]
Leissring, M. A., Farris, W., Chang, A. Y., Walsh, D. M., Wu, X., Sun, X., Frosch, M. P., Selkoe, D. J. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 40: 1087-1093, 2003. [PubMed: 14687544] [Full Text: https://doi.org/10.1016/s0896-6273(03)00787-6]
Letarte, M., Vera, S., Tran, R., Addis, J. B. L., Onizuka, R. J., Quackenbush, E. J., Jongeneel, C. V., McInnes, R. R. Common acute lymphocytic leukemia antigen is identical to neutral endopeptidase. J. Exp. Med. 168: 1247-1253, 1988. [PubMed: 2971756] [Full Text: https://doi.org/10.1084/jem.168.4.1247]
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Pardossi-Piquard, R., Dunys, J., Kawarai, T., Sunyach, C., Alces da Costa, C. A., Vincent, B., Sevalle, J., Pimplikar, S., St. George-Hyslop, P., Checler, F. Response to correspondence: Pardossi-Piquard et al., 'Presenilin-dependent transcriptional control of the A-beta-degrading enzyme neprilysin by intracellular domains of beta-APP and APLP.' Neuron 46, 541-554. Neuron 53: 483-486, 2007. [PubMed: 17296550] [Full Text: https://doi.org/10.1016/j.neuron.2007.01.024]
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Wisner, A., Dufour, E., Messaoudi, M., Nejdi, A., Marcel, A., Ungeheuer, M.-N., Rougeot, C. Human opiorphin, a natural antinociceptive modulator of opioid-dependent pathways. Proc. Nat. Acad. Sci. 103: 17979-17984, 2006. [PubMed: 17101991] [Full Text: https://doi.org/10.1073/pnas.0605865103]