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Two de novo mutations of MFN2 associated with early-onset Charcot-Marie-Tooth disease type 2A neuropathy

Nakhro, Khriezhanuo, Kim, Ye Jin, Lee, Ja Hyun, Koo, Heasoo, Choi, Byung-Ok, Chung, Ki Wha
Genes & genomics 2012 v.34 no.6 pp. 653-661
databases, disease prevalence, genes, guanosinetriphosphatase, human diseases, mitochondria, mutation, nationalities and ethnic groups, patients, peripheral nervous system diseases, phenotype, reproduction
Charcot-Marie-Tooth disease type 2A (CMT2A) is one of the subdivisions of CMT2, an axonal defective form of peripheral neuropathy. Different mutations in the mitochondrial GTPase mitofusin 2 (MFN2) gene produce various degrees of severity of CMT2A phenotype or CMT2A related hereditary motor and sensory neuropathy VI (HMSN VI). The occurrence of de novo mutations in MFN2 is by far the most frequent as compared to other CMT genes. About 26% of the pathogenic MFN2 mutations reported in the Inherited Peripheral Neuropathies Mutations Database are de novo. This study identified two de novo mutations of MFN2, c.1048T>C (S350P) and c.310C>T (R104W), from two Korean CMT2A patients with early onset severe clinical symptoms. The comparative genotype-phenotype correlations of these mutations according to a previously reported case were also viewed. The R104W mutation has been reported recurrently, outspread over different ethnic backgrounds as de novo. The re-occurrence of the same pathogenic de novo variants within and amongst different ethnic groups clearly suggests a susceptible hot spot for mutation in the MFN2 gene. If the deleterious mutations discourage fitness and reproduction, this negative selection factor should ultimately reduce the prevalence of the disease. It appears that spontaneous de novo mutations in turn seem to be maintaining the disease phenotype’s prevalence.