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
  • 1. Advanced Molecular Epidemiology Research Institute, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan. Electronic address: [email protected].
  • 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: [email protected].
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.