Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations

Hum Mutat. 2017 May;38(5):556-568. doi: 10.1002/humu.23189. Epub 2017 Feb 25.

Abstract

In this study, we describe the phenotypic spectrum of distal hereditary motor neuropathy caused by mutations in the small heat shock proteins HSPB1 and HSPB8 and investigate the functional consequences of newly discovered variants. Among 510 unrelated patients with distal motor neuropathy, we identified mutations in HSPB1 (28 index patients/510; 5.5%) and HSPB8 (four index patients/510; 0.8%) genes. Patients have slowly progressive distal (100%) and proximal (13%) weakness in lower limbs (100%), mild lower limbs sensory involvement (31%), foot deformities (73%), progressive distal upper limb weakness (29%), mildly raised serum creatine kinase levels (100%), and central nervous system involvement (9%). We identified 12 HSPB1 and four HSPB8 mutations, including five and three not previously reported. Transmission was either dominant (78%), recessive (3%), or de novo (19%). Three missense mutations in HSPB1 (Pro7Ser, Gly53Asp, and Gln128Arg) cause hyperphosphorylation of neurofilaments, whereas the C-terminal mutant Ser187Leu triggers protein aggregation. Two frameshift mutations (Leu58fs and Ala61fs) create a premature stop codon leading to proteasomal degradation. Two mutations in HSPB8 (Lys141Met/Asn) exhibited increased binding to Bag3. We demonstrate that HSPB1 and HSPB8 mutations are a major cause of inherited motor axonal neuropathy. Mutations lead to diverse functional outcomes further demonstrating the pleotropic character of small heat shock proteins.

Keywords: distal hereditary motor neuropathy; functional validation of novel mutations; peripheral neuropathies; small heat shock proteins.

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Amino Acid Substitution
  • Biomarkers
  • Cell Line
  • Child
  • DNA Mutational Analysis
  • Female
  • Gene Frequency
  • Genetic Association Studies*
  • Genotype
  • HSP27 Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins, Small / genetics*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Molecular Chaperones
  • Motor Neuron Disease / diagnosis
  • Motor Neuron Disease / genetics
  • Multigene Family
  • Mutation*
  • Phenotype
  • Protein Serine-Threonine Kinases / genetics
  • Young Adult

Substances

  • Biomarkers
  • HSP27 Heat-Shock Proteins
  • HSPB1 protein, human
  • HSPB3 protein, human
  • HSPB8 protein, human
  • Heat-Shock Proteins
  • Heat-Shock Proteins, Small
  • Molecular Chaperones
  • Protein Serine-Threonine Kinases