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

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

  • Am J Hum Genet. 2014 Sep 4;95(3):294-300. doi: 10.1016/j.ajhg.2014.07.013.
Gen Tamiya 1,  Satoshi Makino 2,  Makiko Hayashi 3,  Akiko Abe 3,  Chikahiko Numakura 3,  Masao Ueki 2,  Atsushi Tanaka 4,  Chizuru Ito 5,  Kiyotaka Toshimori 5,  Nobuhiro Ogawa 6,  Tomoya Terashima 6,  Hiroshi Maegawa 6,  Daijiro Yanagisawa 7,  Ikuo Tooyama 7,  Masayoshi Tada 8,  Osamu Onodera 8,  Kiyoshi Hayasaka 9
Affiliations

Affiliations

  • 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.
PMID: 25152455 DOI: 10.1016/j.ajhg.2014.07.013
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.

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