Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study

Brain. 2008 May;131(Pt 5):1217-27. doi: 10.1093/brain/awn029. Epub 2008 Mar 5.

Abstract

Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Chromosomes, Human, Pair 11 / genetics
  • Electrophysiology
  • Female
  • GTP-Binding Protein gamma Subunits / genetics
  • Genotype
  • HSP27 Heat-Shock Proteins
  • Haplotypes
  • Heat-Shock Proteins / genetics
  • Hereditary Sensory and Motor Neuropathy / genetics*
  • Hereditary Sensory and Motor Neuropathy / physiopathology
  • Humans
  • Male
  • Mosaicism
  • Mutation, Missense*
  • Neoplasm Proteins / genetics
  • Pedigree
  • Phenotype
  • Protein-Serine-Threonine Kinases / genetics
  • RNA Helicases / genetics

Substances

  • BSCL2 protein, human
  • GTP-Binding Protein gamma Subunits
  • HSP27 Heat-Shock Proteins
  • HSPB1 protein, human
  • HSPB8 protein, human
  • Heat-Shock Proteins
  • Neoplasm Proteins
  • Protein-Serine-Threonine Kinases
  • SETX protein, human
  • RNA Helicases