Novel HSPB1 mutation causes both motor neuronopathy and distal myopathy

摘要

Objective: To identify the cause of isolated distal weakness in a family with both neuropathic and myopathic features on EMG and muscle histology. Methods: Case study with exome sequencing in 2 affected individuals, bioinformatic prioritization of genetic variants, and segregation analysis of the likely causal mutation. Functional studies included Western blot analysis of the candidate protein before and after heat shock treatment of primary skin fibroblasts. Results: A novel HSPB1 variant (c.387C>G, p.Asp129Glu) segregated with the phenotype and was predicted to alter the conserved α-crystallin domain common to small heat shock proteins. At baseline, there was no difference in HSPB1 protein levels nor its binding partner αB-crystallin. Heat shock treatment increased HSPB1 protein levels in both patient-derived and control fibroblasts, but the associated increase in αB-crystallin expression was greater in patient-derived than control fibroblasts. Conclusions: The HSPB1 variant (c.387C>G, p.Asp129Glu) is the likely cause of distal neuromyopathy in this pedigree with pathogenic effects mediated through binding to its partner heat shock protein αB-crystallin. Mutations in HSBP1 classically cause a motor axonopathy, but this family shows that the distal weakness can be both myopathic and neuropathic. The traditional clinical classification of distal weakness into “myopathic” or “neuropathic” forms may be misleading in some instances, and future treatments need to address the pathology in both tissues. In the absence of other phenotypic features, the differential diagnosis of distal lower limb weakness with atrophy can be challenging. Clinical investigations are used to distinguish primary distal myopathies from a pure neurogenic disorder in an attempt to narrow down the differential diagnosis for targeted genetic analysis. Distal hereditary motor neuropathies are genetically heterogeneous and often overlapping with axonal forms of Charcot-Marie-Tooth disease, adding further complexity to the diagnostic approach. Here, we describe a family with late-onset weakness of the distal lower limbs. EMG and pathologic analysis showed evidence of both primary myopathy and motor neuropathy. Exome sequencing identified a novel mutation in the conserved α-crystallin domain of HSPB1 affecting expression levels of its binding partner αB-crystallin following heat shock. The multiple tissues involved in this disorder are important for both the clinical classification of distal weakness and the development of new treatments.