The Mutational Spectrum in a Cohort of Charcot-Marie-Tooth Disease Type 2 among the Han Chinese in Taiwan

Abstract

BackgroundCharcot-Marie-Tooth disease type 2 (CMT2) is a clinically and genetically heterogeneous group of inherited axonal neuropathies. The aim of this study was to extensively investigate the mutational spectrum of CMT2 in a cohort of patients of Han Chinese.Methodology and Principal FindingsGenomic DNA from 36 unrelated Taiwanese CMT2 patients of Han Chinese descent was screened for mutations in the coding regions of the MFN2, RAB7, TRPV4, GARS, NEFL, HSPB1, MPZ, GDAP1, HSPB8, DNM2, AARS and YARS genes. Ten disparate mutations were identified in 14 patients (38.9% of the cohort), including p.N71Y in AARS (2.8%), p.T164A in HSPB1 (2.8%), and p.[H256R]+[R282H] in GDAP1 (2.8%) in one patient each, three NEFL mutations in six patients (16.7%) and four MFN2 mutations in five patients (13.9%). The following six mutations were novel: the individual AARS, HSPB1 and GDAP1 mutations and c.475-1G>T, p.L233V and p.E744M mutations in MFN2. An in vitro splicing assay revealed that the MFN2 c.475-1G>T mutation causes a 4 amino acid deletion (p.T159_Q162del). Despite an extensive survey, the genetic causes of CMT2 remained elusive in the remaining 22 CMT2 patients (61.1%).Conclusions and SignificanceThis study illustrates the spectrum of CMT2 mutations in a Taiwanese CMT2 cohort and expands the number of CMT2-associated mutations. The relevance of the AARS and HSPB1 mutations in the pathogenesis of CMT2 is further highlighted. Moreover, the frequency of the NEFL mutations in this study cohort was unexpectedly high. Genetic testing for NEFL and MFN2 mutations should, therefore, be the first step in the molecular diagnosis of CMT2 in ethnic Chinese.

A novel AARS mutation in a family with dominant myeloneuropathy

“…A different mutation, p.Asn71Tyr, was found in a large Chinese family that was said to have late-onset, mild CMT2, but the relevant clinical and electrophysiologic findings demonstrating sensory axon involvement, and thus justifying the diagnosis of CMT2, were not reported. 7 Thus, the p.Asn71Tyr mutation could be a distal hereditary motor neuropathy, which was the reported phenotype of the p.Asp893Asn mutation in another Chinese family. 29 Like the p.Gly102Arg mutation, the p. Asn71Tyr and the p.Arg329His mutations affect highly conserved amino acids.…”

NEFL N98S mutation: another cause of dominant intermediate Charcot–Marie–Tooth disease with heterogeneous early-onset phenotype

“…NEFL mutations have occasionally been associated with intermediately slowed MCV [16,20,21], just one pedigree having been reported under the rubric of DI-CMT [8]. As a whole, NEFL mutations represent between 0.8 and 2 % of all patients with CMT [15,18,[22][23][24][25]. NEFL-associated CMT is a highly variable disorder that comprises more than 18 disease-causing mutations, targeting the head or rod protein domains, with highly variable phenotypic expression, N98S (N97 in the old nomenclature) being reported in five pedigrees with severe early-onset disease phenotype [15,19,26,27].…”

Charcot–Marie–Tooth diseases: an update and some new proposals for the classification

“…Among CMT2 patients, the most frequent mutated gene is MFN2 and, at the present time, it is said to account for 10–30% of these cases; otherwise, mutations in NEFL gene have been recently found as unexpectedly frequent in CMT2 patients of Chinese origin 33. Concerning AR forms, many of the reported families and patients originated from Mediterranean countries as a consequence of the high rate of consanguinity (especially in Maghreb and the Middle East).…”