MFN2 is located on the short arm of chromosome 1. It encodes mitofusin 2, a GTPase dynamin-like protein of the outer mitochondria membrane.
MFN2 has an essential role in mitochondrial functions including fusion, axonal transport, interorganellar communication and mitophagy [
5,
6]. Because mitochondria are crucial organelles present in almost all cells of human body (except erythrocyte) to provide ATP for metabolic processes and oxidative phosphorylation [
9], mutations of
MFN2 may cause mitochondria dysfunction and affect high energetic demand tissues. Since the first heterozygous mutation in the
MFN2 has been found by Züchner et al in 2004, more than 100
MFN2 mutations have been reported to be associated with CMT [
6,
7,
10]. Based on the existing reports, these mutations can be either gain or loss of function in mitochondria. In some cases, certain
MFN2 mutations are associated with specific clinical features [
11]. c.730G > A (p.Val244Met), a mutation occurring at the same position as the one reported in this study, has been reported to cause CMT2 by K.Kijima et al in 2005. The Japanese kid with the c.730G > A mutation showed CMT2 phenotype with no sensory impairments. The age of onset was 10 months and the symptom included walking difficulties [
8]. In our study, the patient’s symptom at the onset was abnormal gait when he started to walk at the age of 1 year and 7 to 8 months. Then he showed running difficulties, frequent falls and slowly progressive atrophy of lower legs with a mild deformity at his left foot. On the other side, this boy did have sensory loss at his lower limbs. All of these symptoms agree with CMT phenotypes. Because of his median nerve conduction velocity is 50.0 m/s (>38 m/s), we classified it as CMT2.
Based on previously reports and the clinical symptoms of the patient, we believe that the novel
MFN2 mutation identified in this study has a deleterious nature and is the likely cause of CMT2 for the following reasons:. First, the c.730G > C mutation changes an amino acid from valine to leucine and may affect protein features. Second, p.Val244Leu in
MFN2 was predicted to be disease-causing by all three computational tools (Mutation Taster, PROVEAN and SIFT). Third, this mutation changed an evolutionarily conserved amino acid (Phylop score is 5.51) (Table
3). Four, according to previous reports, there is one CMT2A disease causing mutation at the same position (c.730G > A/p.Val244Met). In summary, the
de novo pattern is consistent with the previously reported autosomal dominant inheritance of CMT2A2.
Table 3
Multi-species sequence alignment showing the evolutionarily conserved residues of p.V244 in MFN2