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Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet

Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
Human Genetics (Impact Factor: 4.52). 02/2005; 116(1-2):23-7. DOI: 10.1007/s00439-004-1199-2
Source: PubMed

ABSTRACT Charcot-Marie-Tooth disease (CMT) has been classified into two types, CMT1 and CMT2, demyelinating and axonal forms, respectively. CMT2 has been further subdivided into eight groups by linkage studies. CMT2A is linked to chromosome 1p35-p36 and mutation in the kinesin family member 1B-beta (KIF1B) gene had been reported in one pedigree. However, no mutation in KIF1B was detected in other pedigrees with CMT2A and the mutations in the mitochondrial fusion protein mitofusin 2 (MFN2) gene were recently detected in those pedigrees. MFN2, a mitochondrial transmembrane GTPase, regulates the mitochondrial network architecture by fusion of mitochondria. We studied MFN2 in 81 Japanese patients with axonal or unclassified CMT and detected seven mutations in seven unrelated patients. Six of them were novel and one of them was a de novo mutation. Most mutations locate within or immediately upstream of the GTPase domain or within two coiled-coil domains, which are critical for the functioning or mitochondrial targeting of MFN2. Formation of a mitochondrial network would be required to maintain the functional peripheral nerve axon.

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    • "Marf encodes the Drosophila homolog of the mitochondrial fusion GTPase, Mitofusin 1 and 2 (Debattisti and Scorrano, 2013). Mutations in MFN2 cause Charcot-Marie- Tooth disease type 2A2 (CMT2-A2), an autosomal dominant adult onset peripheral neuropathy (Kijima et al., 2005) as well as Hereditary motor and sensory neuropathy VI (HMSN6) (Del Bo et al., 2008). Lastly, Aats-met is the Drosophila homolog of mitochondrial methionyl-tRNA synthetase 2, or MARS2. "
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    • "The MFN2 T236M mutation was previously reported in a child with moderate neuropathy with onset at the age of 7 who had asymptomatic parents. It is not clear if it was a de novo mutation (Kijima et al., 2005). The phenotypes of our proband's mother and his maternal grandfather confirm the pathogenicity, albeit weak, of MFN2 T236M. "
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    • "For diseases that affect basic neurobiologial functions, mtDNA tRNA mutations may affect processes beyond mitochondrial translation , including the mitochondrial inner membrane (MIM) lipid environment, dynamics, maintenance, and replication machinery (Dimauro et al., 2013). Mutations in mitofusin, a protein responsible for mitochondrial fusion and fission, cause the peripheral neuropathy disease Charcot-Marie-Tooth (CMT) type 2A (Zuchner et al., 2004; Kijima et al., 2005). In a zebrafish model, the loss-of-function mutation demonstrated that indeed transport of mitochondria along the axon is disrupted and may be the contributing factor in the CMT2A phenotype (Chapman et al., 2013). "
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