A nonsense mutation in MME gene associates with autosomal recessive late‐onset Charcot–Marie–Tooth disease

Background: The genetic cause for the majority of patients with late-onset axonal form of neuropathies have remained unknown. In this study we aimed to identify the causal mutation in a family with multiple affected individuals manifesting a range of phenotypic features consistent with late-onset sensorimotor axonal polyneuropathy. Methods: Whole exome sequencing (WES) followed by targeted variant screening and prioritization was performed to identify the candidate mutation. The co-segregation of the mutation with the phenotype was confirmed by Sanger sequencing. Results: We identified a nonsense mutation (c.1564C>T; p.Q522*) in membrane metalloendopeptidase (MME) gene as the cause of the disease condition. The mutation has a combined annotation- dependent depletion (CADD) score 45 and predicted to be deleterious based on various algorithms. The mutation was inherited in an autosomal recessive mode and further confirmed to co-segregate with the disease phenotype in the family and showed to has the required criteria including rarity and deleteriousness to be considered as pathogenic. Conclusion: The MME gene encodes for the membrane bound endopeptidase neprilysin (NEP) which is involved in processing of various peptide substrates. The identified mutation causes a complete loss of carboxy-terminal region of the NEP protein which contains the zinc binding site and the catalytic domain and thus considered to be a loss-of-function mutation. The loss of NEP activity is likely associated with impaired myelination and axonal injury which is hallmark of CMT diseases.