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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- "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.
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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 · 2.50 Impact Factor
- "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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ABSTRACT: Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA) genes are "hotspots" for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase), mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation (e.g., splicing). Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.Frontiers in Genetics 06/2014; 5:158. DOI:10.3389/fgene.2014.00158