Nonsense mutations in alpha-II spectrin in three families with juvenile onset hereditary motor neuropathy

Brain. 2019 Sep 1;142(9):2605-2616. doi: 10.1093/brain/awz216.

Abstract

Distal hereditary motor neuropathies are a rare subgroup of inherited peripheral neuropathies hallmarked by a length-dependent axonal degeneration of lower motor neurons without significant involvement of sensory neurons. We identified patients with heterozygous nonsense mutations in the αII-spectrin gene, SPTAN1, in three separate dominant hereditary motor neuropathy families via next-generation sequencing. Variable penetrance was noted for these mutations in two of three families, and phenotype severity differs greatly between patients. The mutant mRNA containing nonsense mutations is broken down by nonsense-mediated decay and leads to reduced protein levels in patient cells. Previously, dominant-negative αII-spectrin gene mutations were described as causal in a spectrum of epilepsy phenotypes.

Keywords: alpha-II-spectrin; distal hereditary motor neuropathies; next-generation sequencing; nonsense mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carrier Proteins / genetics*
  • Child
  • Codon, Nonsense / genetics*
  • Cohort Studies
  • Female
  • Humans
  • Male
  • Microfilament Proteins / genetics*
  • Middle Aged
  • Mutation / genetics*
  • Pedigree
  • Peripheral Nervous System Diseases / diagnosis*
  • Peripheral Nervous System Diseases / genetics*
  • Young Adult

Substances

  • Carrier Proteins
  • Codon, Nonsense
  • Microfilament Proteins
  • fodrin

Supplementary concepts

  • Inherited Peripheral Neuropathy