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A novel p.Val244Leu mutation in MFN2 leads to Charcot-Marie-Tooth disease type 2.

ABSTRACT: Charcot-Marie-Tooth (CMT) disease is one of the most common hereditary peripheral neuropathy. The major clinical features of CMT are progressive muscle weakness of distal extremities and sensory loss. MFN2 encodes a GTPase dynamin-like protein mitofusin 2 and plays an essential role in mitochondrial functions. In previous studies, MFN2 mutations have been linked to neurological disorders including CMT type 2 (CMT2). Here, we report a novel mutation in MFN2 which leads to CMT 2.We report a 4-year-old Chinese boy with CMT symptoms including foot-drop gait, running difficulties, frequent falls, slowly progressive atrophy of lower legs with a mildly foot deformity. Nerve conduction velocity study (NCVS) found that no compound motor action potential (CMAP) was elicited in the nervi suralis and tibial nerve. Moreover, the sensory nerve action potential (SNAP) of the nervi suralis was not elicited, which means the peripheral nerves of his lower limbs were damaged. Targeted next-generation sequencing identified a novel heterozygous mutation c.730G?>?C (p.Val244Leu) in MFN2 in the patient but not in his parents, suggesting that this mutation likely occurred de novo. c.730G?>?C (p.Val244Leu) in MFN2 is a likely pathogenic mutation for CMT2.The c.730G?>?C (p.Val244Leu) mutation in MFN2 is a likely pathogenic mutation for CMT2.

SUBMITTER: Yang Y

PROVIDER: S-EPMC4784292 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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A novel p.Val244Leu mutation in MFN2 leads to Charcot-Marie-Tooth disease type 2.

Yang Yuan Y Li Ling L

Italian journal of pediatrics 20160308

<h4>Background</h4>Charcot-Marie-Tooth (CMT) disease is one of the most common hereditary peripheral neuropathy. The major clinical features of CMT are progressive muscle weakness of distal extremities and sensory loss. MFN2 encodes a GTPase dynamin-like protein mitofusin 2 and plays an essential role in mitochondrial functions. In previous studies, MFN2 mutations have been linked to neurological disorders including CMT type 2 (CMT2). Here, we report a novel mutation in MFN2 which leads to CMT 2 ...[more]

PMID: 26956144

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Project description:RationaleCharcot-Marie-Tooth disease (CMT) is a group of hereditary neuropathies with clinical features of muscle atrophy, sensory loss, and foot deformities. CMT is related to a number of genes, such as peripheral myelin protein 22 gene (PMP22). Missense mutations, small deletion mutations, and duplications of PMP22 are common in CMT patients, but few insertion mutation cases of PMP22 have been reported.Patient concernsA 26-year-old male patient with the complaint of general weakness, peroneal atrophy, and deformities in the extremities visited our hospital. The patient was born with bilateral thumbs and feet dystonia. Additionally, delayed feet arch development and delayed walking was observed when he was a child.DiagnosisUsing whole-exome sequencing and electrophysiological test, we identified a novel insertion mutation of PMP22 (NM_153322, c.54_55insGTGCTG, p.(L19delinsVLL)) in a 26-year-old male patient with peroneal atrophy and nerve conduction was not elicited in electromyography (EMG) study. The Protein Variation Effect Analyzer (PROVEAN) program analysis predicted that the variant is likely to be "deleterious." SWISS-MODEL program predicted that alpha helix in original location was disrupted by inserted 6 bases, which may account for the occurrence of CMT3.InterventionsThe patient received symptomatic and supportive treatments, and routine rehabilitation exercises during hospitalization.OutcomesThe condition of the patient was improved, but the disease could not be cured. At 1- and 3-months follow-up, manifestations of the patient were unchanged, and he could take care of himself.LessonsOur findings link a novel PMP22 mutation with a clinical diagnosis of CMT3. The link between gene variation and CMT phenotype may help to reveal the structure and function of PMP22 protein and the pathogenesis of CMT. This study adds further support to the heterogeneity of PMP22 related CMT and provides solid functional evidence for the pathogenicity of the p.(L19delinsVLL) PMP22 variant. Moreover, with the development of high-throughput sequencing technology, the combination of next-generation sequencing (NGS) and conventional Sanger sequencing is becoming one of the comprehensive, inexpensive, and convenient tools for genetic diagnosis of CMT.

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A novel p.Val244Leu mutation in MFN2 leads to Charcot-Marie-Tooth disease type 2.

Publications

A novel p.Val244Leu mutation in MFN2 leads to Charcot-Marie-Tooth disease type 2.

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