Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet
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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- "GJB1 encodes a gap junction protein involved in the formation of connexon hemichannels that facilitate the communication and exchange of ions and other small molecules between Schwann cells and axons (Scherer and Kleopa, 2012). The third most common cause of CMT, and the most common form of CMT2, are heterozygous mutations in MFN2 (CMT2A; MIM #609260) (Ben Othmane et al., 1993; Zü chner et al., 2004; Verhoeven et al., 2006), essential for mitochondrial fusion and function (Kijima et al., 2005) and maintenance of mitochondrial morphology. Mutations in MFN2 lead to mitochondrial dysfunction due to mtDNA depletion (Vielhaber et al., 2013). "
ABSTRACT: Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.Cell Reports 08/2015; 12(7). DOI:10.1016/j.celrep.2015.07.023 · 8.36 Impact Factor
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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. "
ABSTRACT: Reactive oxygen species (ROS) and mitochondrial defects in neurons are implicated in neurodegenerative disease. Here, we find that a key consequence of ROS and neuronal mitochondrial dysfunction is the accumulation of lipid droplets (LD) in glia. In Drosophila, ROS triggers c-Jun-N-terminal Kinase (JNK) and Sterol Regulatory Element Binding Protein (SREBP) activity in neurons leading to LD accumulation in glia prior to or at the onset of neurodegeneration. The accumulated lipids are peroxidated in the presence of ROS. Reducing LD accumulation in glia and lipid peroxidation via targeted lipase overexpression and/or lowering ROS significantly delays the onset of neurodegeneration. Furthermore, a similar pathway leads to glial LD accumulation in Ndufs4 mutant mice with neuronal mitochondrial defects, suggesting that LD accumulation following mitochondrial dysfunction is an evolutionarily conserved phenomenon, and represents an early, transient indicator and promoter of neurodegenerative disease. Copyright © 2015 Elsevier Inc. All rights reserved.Cell 01/2015; 160(1-2):177-90. DOI:10.1016/j.cell.2014.12.019 · 32.24 Impact Factor
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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. "
ABSTRACT: The aim of our study was to electrophysiologically characterize and explain the genetic cause of severe CMT in a 3.5-year-old with asymptomatic parents and a maternal grandfather with a history of mild adult-onset axonal neuropathy. Severity of neuropathy was assessed by Charcot-Marie-Tooth neuropathy score (CMTNS). Whole exome sequencing (WES) was performed using an Illumina TruSeq Exome Enrichment Kit on the HiSeq 1500 with results followed up by Sanger sequencing on an ABI Prism 3500XL. Paternity was confirmed using a panel of 15 hypervariable markers. Electrophysiological studies demonstrated severe axonal sensory-motor neuropathy in the proband, mild motor neuropathy in his mother and mild sensory-motor neuropathy in his grandfather. CMTNS in the proband, his mother and grandfather was 21, 1 and 12, respectively. On genetic analysis the boy was found to carry a heterozygous dominant MFN2 T236M mutation transmitted via the maternal line and a de novo GDAP1 H123R mutation. Our findings emphasize the need to search for more than one causative mutation when significant intrafamilial variability of CMT phenotype occurs, and underlines the role of whole exome sequencing in the diagnosis of compound forms of Charcot-Marie-Tooth disease.Journal of the Peripheral Nervous System 11/2014; 19(3). DOI:10.1111/jns.12088 · 2.76 Impact Factor