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. Epub 2014 Aug 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • COX6A1 protein, human
  • Cox6a1 protein, mouse
  • Electron Transport Complex IV