Delineation of C12orf65-related phenotypes: a genotype-phenotype relationship

Eur J Hum Genet. 2014 Aug;22(8):1019-25. doi: 10.1038/ejhg.2013.284. Epub 2014 Jan 15.

Abstract

C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families. In four family members affected with childhood-onset optic atrophy accompanied by slowly progressive peripheral neuropathy and spastic paraparesis, we identified a homozygous frame shift mutation c.413_417 delAACAA, which predicts a truncated protein lacking the C-terminal portion. In the second family, we studied three affected individuals who presented with early onset optic atrophy, peripheral neuropathy, and spastic gait in addition to moderate intellectual disability. Muscle biopsy in two of the patients revealed decreased activities of the mitochondrial respiratory chain complexes I and IV. In these patients, we identified a homozygous splice mutation, g.21043 T>A (c.282+2 T>A) which leads to skipping of exon 2. Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features. In addition, a clear genotype-phenotype correlation is anticipated in which deleterious mutations which disrupt the GGQ-containing domain in the first coding exon are expected to result in a more severe phenotype, whereas down-stream C-terminal mutations may result in a more favorable phenotype, typically lacking cognitive impairment.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alternative Splicing
  • Amino Acid Sequence
  • Brain / pathology
  • Child
  • Consanguinity
  • DNA Mutational Analysis
  • Electron Transport Complex IV / metabolism
  • Female
  • Genetic Association Studies*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Mitochondrial Proteins / genetics*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Mutation*
  • Optic Atrophy / genetics
  • Pedigree
  • Peptide Termination Factors / genetics*
  • Phenotype*
  • Young Adult

Substances

  • C12orf65 protein, human
  • Mitochondrial Proteins
  • Peptide Termination Factors
  • Electron Transport Complex IV