Submission Details

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.