Late Onset Spinal Motor Neuronopathy Is Caused by Mutation in CHCHD10

Ann Neurol. 2015 Jan;77(1):163-72. doi: 10.1002/ana.24319. Epub 2014 Dec 12.

Abstract

Objective: A study was undertaken to identify the responsible gene defect underlying late onset spinal motor neuronopathy (LOSMoN/SMAJ; Online Mendelian Inheritance in Man #615048), an autosomal dominant disease mapped to chromosome 22q11.2.

Methods: The previous genetic linkage approach by microsatellite haplotyping was continued in new families. A whole genome sequencing was performed to find all possibly pathogenic mutations in the linked area. The detected variations were verified by Sanger sequencing.

Results: Six new SMAJ families were identified based on the unique founder haplotype. A critical recombination in 1 family restricted the linked area to 727kb between markers SHGC-106816 and D22S345. In whole genome sequencing a previously unknown mutation c.197G>T p.G66V in CHCHD10 was identified. The mutation was shown to segregate with the disease in 55 patients from 17 families.

Interpretation: Mutation c.197G>T p.G66V in CHCHD10 is the cause of the lower motor neuron syndrome LOSMoN/SMAJ. During the preparation of this article other mutations were reported to cause frontotemporal dementia-amyotrophic lateral sclerosis syndrome, indicating that the CHCHD10 gene is largely important for the motor and cognitive neuronal systems.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Family Health
  • Female
  • Finland
  • Genetic Association Studies
  • Genetic Linkage
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Mitochondrial Proteins / genetics*
  • Muscular Atrophy, Spinal / genetics*
  • Mutation / genetics*
  • Young Adult

Substances

  • CHCHD10 protein, human
  • Mitochondrial Proteins