The MFN2 V705I Variant Is Not a Disease-Causing Mutation: A Segregation Analysis in a CMT2 Family

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of disorders affecting both motor and sensory neurons in the peripheral nervous system. Mutations in the MFN2 gene cause an axonal form of CMT, CMT2A. The V705I variant in MFN2 has been previously reported as a disease-causing mutation in families with CMT2. We identified an affected index patient from an Australian multigenerational family with the V705I variant. Segregation analysis showed that the V705I variant did not segregate with the disease phenotype and was present in control individuals with an allele frequency of 4.4%. We, therefore, propose that the V705I variant is a polymorphism and not a disease-causing mutation as previously reported. 1. Introduction Charcot-Marie-Tooth (CMT), also known as hereditary motor and sensory neuropathy, is classified into two major categories: type 1 and type 2 based on the value of motor median nerve conduction velocity (NCV) [1]. CMT1, also known as the demyelinating form of CMT, is clinically characterized by slow NCVs due to myelin sheath abnormalities. CMT2 is as an axonal degeneration and is characterized by the reduction of the amplitudes of motor and sensory nerve action potentials with relatively normal conduction velocities [2]. The most common subtype of CMT2 is CMT2A, an autosomal dominant axonal degeneration of motor and sensory nerves caused by mutations in the mitochondrial mitofusin-2 (MFN2) gene (MIM 608507) [3]. Mutations in the MFN2 gene are the most common cause for CMT2 [2–6]. MFN2 is involved in mitochondrial fusion and the maintenance of mitochondrial morphology [7–9]. Numerous studies have reported mutations in the MFN2 gene; the majority are point mutations [10]. We have identified the single base change c.2113G > A changing valine to isoleucine (V705I) of the MFN2 gene in a patient from a multigenerational Australian family (CMT105) with CMT2 and pyramidal signs. The V705I variant of MFN2 has been previously reported as a disease causing mutation in single individuals with CMT2 [11, 12]. To determine if this variant causes CMT2 in the family, we performed segregation analysis and tested the variant in a cohort of ethnically matched controls of English descent. 2. Methods 2.1. Subjects Thirty-two individuals from a large, multigeneration Australian CMT2 family (CMT105) were tested (Figure 1). Sixteen individuals were clinically affected. Informed consent was obtained from all participants according to protocols approved by the Sydney Local Health District Human Ethics Committee. Genomic DNA was