RRC ID 45247
Author Tamiya G, Makino S, Hayashi M, Abe A, Numakura C, Ueki M, Tanaka A, Ito C, Toshimori K, Ogawa N, Terashima T, Maegawa H, Yanagisawa D, Tooyama I, Tada M, Onodera O, Hayasaka K.
Title A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
Journal Am. J. Hum. Genet.
Abstract Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy characterized by clinical and genetic heterogeneity. Although more than 30 loci harboring CMT-causing mutations have been identified, many other genes still remain to be discovered for many affected individuals. For two consanguineous families with CMT (axonal and mixed phenotypes), a parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb region on 12q24 showing a maximum multipoint LOD score of 4.23. Subsequent whole-genome sequencing study in one of the probands, followed by mutation screening in the two families, revealed a disease-specific 5 bp deletion (c.247-10_247-6delCACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase [COX]), within the autozygous linkage region. Functional analysis showed that expression of COX6A1 in peripheral white blood cells from the affected individuals and COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced. In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking. Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT.
Volume 95(3)
Pages 294-300
Published 2014-9-4
DOI 10.1016/j.ajhg.2014.07.013
PII S0002-9297(14)00322-X
PMID 25152455
PMC PMC4157141
MeSH Adult Animals Axons / physiology* Charcot-Marie-Tooth Disease / genetics* Consanguinity Electron Transport Complex IV / genetics* Electron Transport Complex IV / physiology* Electrophysiology Female Genes, Recessive / genetics* Genetic Linkage Humans Lod Score Male Mice Mice, Knockout Muscular Atrophy / genetics* Mutation / genetics* Pedigree Phenotype RNA Splicing / genetics
IF 9.924
Times Cited 16
Human and Animal Cells