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Am J Hum Genet. 2014 Sep 4;95(3):294-300. doi: 10.1016/j.ajhg.2014.07.013. Epub 2014 Aug 21.

A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.

Author information

1
Advanced Molecular Epidemiology Research Institute, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan. Electronic address: gtamiya@genetix-h.com.
2
Advanced Molecular Epidemiology Research Institute, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
3
Department of Pediatrics, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
4
Research Institute of Medical Sciences, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
5
Department of Reproductive Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
6
Department of Medicine, Shiga University of Medical Science, Otsu 520-2192, Japan.
7
Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu 520-2192, Japan.
8
Department of Molecular Neuroscience, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
9
Department of Pediatrics, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan. Electronic address: hayasaka@med.id.yamagata-u.ac.jp.

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.

PMID:
25152455
PMCID:
PMC4157141
DOI:
10.1016/j.ajhg.2014.07.013
[Indexed for MEDLINE]
Free PMC Article

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