A novel p.T139M mutation in HSPB1 highlighting the phenotypic spectrum in a family

INTRODUCTION: Mutations in the HSPB1 gene encoding the small heat shock protein B1 are associated with an autosomal dominant, axonal form of Charcot–Marie–Tooth disease 2F (CMT2F) and distal hereditary motor neuropathy. Recently, distal myopathy had been described in a patient carrying HSPB1 mutation adding to the complexity of phenotypes resulting from HSPB1 mutations. METHODS: Five patients in a family with concerns of hereditary neuropathy were included. Detailed clinical examinations, including assessments of motor and sensory function, and electrophysiological data were obtained. Genetic analysis was requested through a commercial laboratory. In vitro studies were carried out to assess the pathogenicity of the novel mutation found in this family studies. RESULTS: All patients carried a novel mutation, c.146 C>T (p.T139M), substitution in the α‐crystallin domain of HSPB1 causing a clinical phenotype with hyperreflexia and intrafamilial variability, from muscle cramps as the only presenting symptom to a classic CMT phenotype. In vitro studies showed that cells expressing HSPB1‐T139M displayed decreased cell viability with increased expression of apoptosis markers. Moreover, overexpression of the mutant, not the wild‐type HSPB1, caused formation of congophilic aggregates. CONCLUSIONS: In vitro findings strongly support the pathogenicity of this novel mutation. We propose that Congo red histochemical stain may serve as a simple screening tool for investigating if the aggregates in mutant cells have misfolded β‐pleated sheet secondary structures.