MME
protein-codingmembrane metalloendopeptidase, the group of CD molecules|M13 metallopeptidases
Gene summary
The protein encoded by this gene is a type II transmembrane glycoprotein and a common acute lymphocytic leukemia antigen that is an important cell surface marker in the diagnosis of human acute lymphocytic leukemia (ALL). The encoded protein is present on leukemic cells of pre-B phenotype, which represent 85% of cases of ALL. This protein is not restricted to leukemic cells, however, and is found on a variety of normal tissues. The protein is a neutral endopeptidase that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin. [provided by RefSeq, Aug 2017]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~159.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014867
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014866
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014867
Submitter: Orphanet
Inheritance Pattern: SD
Disease ID:MONDO:0014866
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0019068
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014867
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014866
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0044640
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0044640
Submitter: ClinGen
MME encodes the membrane metallo endopeptidase, an ectoenzyme that catalyzes peptide hydrolysis in the extracellular surface. MME was first reported in relation to Autosomal Recessive CMT2 in 2016 (Higuchi et al., PMID: 26991897), followed by additional reports from Lupo (Lupo et al., 2018 PMID 30415211) and Hong (Hong et al., 2019 PMID 31429185). The described phenotype consisted in a slowly progressive neuropathy with distal weakness and atrophy follower by sensory involvement in the form of superficial and deep sensory loss, and no signs of central nervous system involvement. MME has also been associated with Autosomal Dominant SCA43 (Depondt et al., PMID 27583304) and with Autosomal Dominant CMT2 (Auer-Grumbach et al., 2016 PMID: 27588448) however, some of the variants associated with AD-CMT2 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. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanism(s) AND in the inheritance pattern of AR-CMT2 and SCA43. Therefore, the following disease entities have been Split into multiple disease entities, AD-CMT2T (OMIM: 617017) and SCA43 (OMIM: 617018). Twenty-one variants (missense, in-frame indel, nonsense, frameshift) that have been reported in twenty-one probands in three publications (PMIDs: 26991897, 30415211, 31429185) are included in this curation. Variants were detected by WES or illumina sequencing or by custom made panels of CMT genes. Segregation with the disease in additional family members was confirmed in all cases and evidence at a variant level include decrease of enzymatic activity of mutant proteins, abnormal RNA transcript analysis and sural nerve MME staining. All the described biallelic variants have been given the default 0.1 score for missense variants or the default 1.5 score for predicted null variants. With the listed genetic evidence, the maximum score for genetic evidence (12 pts.) has been reached and replicated over time. The mechanism of pathogenicity is hypnotized to be LOF. This gene-disease association is also supported by expression studies, showing expression of MME in the outer surface myelin of normal sural nerve (PMIDs: 8392520) paralleled by decrease or loss of MME expression in the peripheral nerve from affected patients. Homozygous Mme-null mice failed to show any significant phenotype in both behavioral and neurophysiological endpoints. In summary, MME is definitively associated with Autosomal Recessive CMT2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0014866
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:0014866
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0044657
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014867
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MME variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_007289.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 4 | 118 | 1 | 123 | ||
| missense | 11 | 302 | 10 | 323 | ||
| nonsense | 20 | 16 | 2 | 38 | ||
| start loss | 0 | |||||
| frameshift | 25 | 13 | 1 | 39 | ||
| splice donor/acceptor (+/-2bp) | 5 | 27 | 6 | 38 | ||
| Total | 50 | 67 | 315 | 128 | 1 | 561 |
Highest pathogenic variant AF is 0.00032613237
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_009220.2 | 22 | MANE Select | |
| Ensembl | ENSP00000353679.2 | 22 | MANE Select | |
| RefSeq | NP_000893.2 | 22 | Standard | |
| RefSeq | NP_001341571.1 | 22 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Agents Acting on the Renin-Angiotensin System Pathway, Pharmacodynamics
- Renin-angiotensin system - Homo sapiens (human)
- Protein digestion and absorption - Homo sapiens (human)
- Alzheimer,s disease - Homo sapiens (human)
- Hematopoietic cell lineage - Homo sapiens (human)
Biological Process
- kidney development
- angiotensin maturation
- proteolysis
- peptide metabolic process
- sensory perception of pain
Molecular Function
- endopeptidase activity
- metalloendopeptidase activity
- protein binding
- metallopeptidase activity
- exopeptidase activity
Cellular Component
- cytoplasm
- plasma membrane
- integral component of plasma membrane
- brush border
- focal adhesion
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000460393
- Coding exons
- 22
- Length
- 159585
- Individuals with no LoFs
- 125565
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 183
- Defined
- 125748
- p
- 0.000728
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.358 | 374 | 394 | 0.949 | 0.0000205 | 4975 |
| Missense (PolyPhen) | 143 | 159.04 | 0.89916 | 2073 | ||
| Synonymous | 0.672 | 129 | 139 | 0.927 | 0.00000772 | 1312 |
| Loss of Function | 2.00 | 36 | 51.5 | 0.699 | 0.00000285 | 580 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00037 | 0.00037 | rare |
| Latino/Admixed American | 0.0012 | 0.0012 | notable |
| Ashkenazi Jewish | 0.00060 | 0.00060 | rare |
| East Asian | 0.0012 | 0.0012 | notable |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00087 | 0.00086 | rare |
| South Asian | 0.00026 | 0.00026 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids (PubMed:15283675, PubMed:8168535). Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond (PubMed:17101991). Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9 (PubMed:15283675). Involved in the degradation of atrial natriuretic factor (ANF) (PubMed:2531377, PubMed:2972276). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers (PubMed:20876573). {ECO:0000269|PubMed:15283675, ECO:0000269|PubMed:17101991, ECO:0000269|PubMed:20876573, ECO:0000269|PubMed:2531377, ECO:0000269|PubMed:27588448, ECO:0000269|PubMed:2972276}.;
- Disease
- DISEASE: Charcot-Marie-Tooth disease 2T (CMT2T) [MIM:617017]: An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:26991897, ECO:0000269|PubMed:27588448}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spinocerebellar ataxia 43 (SCA43) [MIM:617018]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA43 is a slowly progressive, autosomal dominant form. {ECO:0000269|PubMed:27583304}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.696
Intolerance Scores
- LoFtool
- 0.0163
- RVIS EVS
- -0.69
- RVIS percentile EVS
- 15.32
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.751
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |