title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
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.
authors.affiliation: Advanced Molecular Epidemiology Research Institute, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan. Electronic address: gtamiya@genetix-h.com.
authors.forename: Gen
authors.initials: G
authors.lastname: Tamiya
authors.affiliation: Advanced Molecular Epidemiology Research Institute, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Makino
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Abe
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
authors.forename: Chikahiko
authors.initials: C
authors.lastname: Numakura
authors.affiliation: Advanced Molecular Epidemiology Research Institute, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Ueki
authors.affiliation: Research Institute of Medical Sciences, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Department of Reproductive Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Chizuru
authors.initials: C
authors.lastname: Ito
authors.affiliation: Department of Reproductive Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Toshimori
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu 520-2192, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ogawa
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu 520-2192, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Terashima
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu 520-2192, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
authors.affiliation: Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu 520-2192, Japan.
authors.forename: Daijiro
authors.initials: D
authors.lastname: Yanagisawa
authors.affiliation: Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu 520-2192, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Tooyama
authors.affiliation: Department of Molecular Neuroscience, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Tada
authors.affiliation: Department of Molecular Neuroscience, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan. Electronic address: hayasaka@med.id.yamagata-u.ac.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hayasaka
mesh_terms: D000328:Adult; D000818:Animals; D001369:Axons / Q000502:physiology*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D003241:Consanguinity; D003576:Electron Transport Complex IV / Q000235:genetics* / Q000502:physiology*; D004594:Electrophysiology; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D008040:Genetic Linkage; D006801:Humans; D008126:Lod Score; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009133:Muscular Atrophy / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012326:RNA Splicing / Q000235:genetics
chemical_list: C472626:COX6A1 protein, human; C472628:Cox6a1 protein, mouse; D003576:Electron Transport Complex IV