PT  - JOURNAL ARTICLE
AU  - D.J. Lewis-Smith
AU  - J. Duff
AU  - A. Pyle
AU  - H. Griffin
AU  - T. Polvikoski
AU  - D. Birchall
AU  - R. Horvath
AU  - P.F. Chinnery
TI  - Novel <em>HSPB1</em> mutation causes both motor neuronopathy and distal myopathy
AID  - 10.1212/NXG.0000000000000110
DP  - 2016 Dec 01
TA  - Neurology Genetics
PG  - e110
VI  - 2
IP  - 6
4099  - http://ng.neurology.org/content/2/6/e110.short
4100  - http://ng.neurology.org/content/2/6/e110.full
SO  - Neurol Genet2016 Dec 01; 2
AB  - 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.CK=creatine kinase