A nonsense mutation inMMEgene associates with autosomal recessive late‐onsetCharcot–Marie–Toothdisease

Abstract

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.

A deep intronic variant inMMEcauses autosomal recessive Charcot-Marie-Tooth neuropathy through aberrant splicing

“…Patients are broadly divided into subtypes based on whether nerve conduction studies (NCS) indicating demyelinating (CMT1) or axonal (CMT2) forms of the disease. Recessive loss-of-function variants in the membrane metalloendopeptidase (MME) gene have been previously reported to cause axonal Charcot-Marie-Tooth neuropathy type 2T (CMT2T; OMIM: #617017) [3][4][5][6][7][8][9][10][11] . MME encodes for neprilysin, a widely expressed membranebound metallopeptidase that has a key role in neuropeptide processing 12 .…”

A deep intronic variant in MME causes autosomal recessive Charcot–Marie–Tooth neuropathy through aberrant splicing

“…Recessive lossof-function variants in the membrane metalloendopeptidase (MME) gene have been previously reported to cause axonal Charcot-Marie-Tooth neuropathy type 2T (CMT2T; OMIM: #617017). [3][4][5][6][7][8][9][10][11] MME encodes for neprilysin, a widely expressed membrane-bound metallopeptidase that has a key role in neuropeptide processing. 12 A significant portion of patients with axonal CMT remain genetically undiagnosed, [13][14][15][16][17] indicating that further disease-causing genes and pathogenic variants in known genes are yet to be identified.…”

“…Patients are broadly divided into subtypes based on whether nerve conduction studies (NCS) indicating demyelinating (CMT1) or axonal (CMT2) forms of the disease. Recessive loss‐of‐function variants in the membrane metalloendopeptidase ( MME ) gene have been previously reported to cause axonal Charcot–Marie–Tooth neuropathy type 2T (CMT2T; OMIM: #617017) 3–11 . MME encodes for neprilysin, a widely expressed membrane‐bound metallopeptidase that has a key role in neuropeptide processing 12 .…”

Expanding the Molecular Spectrum of HK1-Related Charcot-Marie-Tooth Disease, Type 4G; the First Report in Iran

“…Given the high prevalence of consanguineous marriages in Iran, ARCMT is expected to be highly prevalent in the Iranian population, and different types of demyelinating or axonal ARCMTs are reported in Iranian patients, such as CMT4A ( GDAP1 gene), CMT4B1 ( MTMR2 gene), CMT4C ( SH3TC2 gene), CMT4D ( NDRG1 gene), CMT4F ( PRX gene), CMT4H ( FGD4 gene), CMT1F ( NEFL gene), CMT2A2B ( MFN2 gene), CMT2S ( IGHMBP2 gene), CMT2T ( MME gene). 9 - 13 …”

“…8 Given the high prevalence of consanguineous marriages in Iran, ARCMT is expected to be highly prevalent in the Iranian population, and different types of demyelinating or axonal ARCMTs are reported in Iranian patients, such as CMT4A (GDAP1 gene), CMT4B1 (MTMR2 gene), CMT4C (SH3TC2 gene), CMT4D (NDRG1 gene), CMT4F (PRX gene), CMT4H (FGD4 gene), CMT1F (NEFL gene), CMT2A2B (MFN2 gene), CMT2S (IGHMBP2 gene), CMT2T (MME gene). [9][10][11][12][13] Here, we present an Iranian 21-year-old female manifesting progressive muscle weakness in distal limbs from 11 years of age who has been diagnosed with chronic demyelinating sensorimotor polyneuropathy. Interestingly, the same homozygous variant described by Kanwal et al, 8 c.19C > T (p. Arg7*) in the HK1 gene, was also detected in this patient.…”