HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum

Neurology. 2014 Nov 4;83(19):1726-32. doi: 10.1212/WNL.0000000000000966. Epub 2014 Oct 1.


Objectives: To determine the nature and frequency of HSJ1 mutations in patients with hereditary motor and hereditary motor and sensory neuropathies.

Methods: Patients were screened for mutations by genome-wide or targeted linkage and homozygosity studies, whole-exome sequencing, and Sanger sequencing. RNA and protein studies of skin fibroblasts were used for functional characterization.

Results: We describe 2 additional mutations in the HSJ1 gene in a cohort of 90 patients with autosomal recessive distal hereditary motor neuropathy (dHMN) and Charcot-Marie-Tooth disease type 2 (CMT2). One family with a dHMN phenotype showed the homozygous splice-site mutation c.229+1G>A, which leads to retention of intron 4 in the HSJ1 messenger RNA with a premature stop codon and loss of protein expression. Another family, presenting with a CMT2 phenotype, carried the homozygous missense mutation c.14A>G (p.Tyr5Cys). This mutation was classified as likely disease-related by several automatic algorithms for prediction of possible impact of an amino acid substitution on the structure and function of proteins. Both mutations cosegregated with autosomal recessive inheritance of the disease and were absent from the general population.

Conclusions: Taken together, in our cohort of 90 probands, we confirm that HSJ1 mutations are a rare but detectable cause of autosomal recessive dHMN and CMT2. We provide clinical and functional information on an HSJ1 splice-site mutation and report the detailed phenotype of 2 patients with CMT2, broadening the phenotypic spectrum of HSJ1-related neuropathies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / genetics
  • Adaptor Proteins, Signal Transducing / genetics
  • Austria
  • Cell Cycle Proteins / genetics
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / pathology
  • Charcot-Marie-Tooth Disease / physiopathology
  • Electromyography
  • Family Health
  • Female
  • Genetic Linkage
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Germany
  • HSP40 Heat-Shock Proteins / genetics*
  • Hereditary Sensory and Motor Neuropathy / genetics*
  • Hereditary Sensory and Motor Neuropathy / pathology
  • Hereditary Sensory and Motor Neuropathy / physiopathology
  • Humans
  • Male
  • Molecular Chaperones / genetics*
  • Mutation / genetics*
  • Neural Conduction / genetics
  • Nuclear Proteins / genetics
  • Phenotype
  • Sequence Analysis, DNA


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • DNAJB2 protein, human
  • HSP40 Heat-Shock Proteins
  • MAD2L1BP protein, human
  • Molecular Chaperones
  • Nuclear Proteins