NovelHSPB1mutation causes both motor neuronopathy and distal myopathy.
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 novelHSPB1variant (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
TheHSPB1variant (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 inHSBP1classically 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.
Institute of Genetic Medicine (D.J.L.-S., J.D., A.P., H.G., R.H., P.F.C.), Institute of Neuroscience (T.P.), Newcastle University; Newcastle upon Tyne Hospitals NHS Foundation Trust (D.J.L.-S., T.P., D.B., R.H.); MRC-Mitochondrial Biology Unit (P.F.C.), Cambridge Biomedical Campus; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
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DJ
Lewis-Smith
Institute of Genetic Medicine (D.J.L.-S., J.D., A.P., H.G., R.H., P.F.C.), Institute of Neuroscience (T.P.), Newcastle University; Newcastle upon Tyne Hospitals NHS Foundation Trust (D.J.L.-S., T.P., D.B., R.H.); MRC-Mitochondrial Biology Unit (P.F.C.), Cambridge Biomedical Campus; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
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J
Duff
Institute of Genetic Medicine (D.J.L.-S., J.D., A.P., H.G., R.H., P.F.C.), Institute of Neuroscience (T.P.), Newcastle University; Newcastle upon Tyne Hospitals NHS Foundation Trust (D.J.L.-S., T.P., D.B., R.H.); MRC-Mitochondrial Biology Unit (P.F.C.), Cambridge Biomedical Campus; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
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A
Pyle
Institute of Genetic Medicine (D.J.L.-S., J.D., A.P., H.G., R.H., P.F.C.), Institute of Neuroscience (T.P.), Newcastle University; Newcastle upon Tyne Hospitals NHS Foundation Trust (D.J.L.-S., T.P., D.B., R.H.); MRC-Mitochondrial Biology Unit (P.F.C.), Cambridge Biomedical Campus; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
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H
Griffin
Institute of Genetic Medicine (D.J.L.-S., J.D., A.P., H.G., R.H., P.F.C.), Institute of Neuroscience (T.P.), Newcastle University; Newcastle upon Tyne Hospitals NHS Foundation Trust (D.J.L.-S., T.P., D.B., R.H.); MRC-Mitochondrial Biology Unit (P.F.C.), Cambridge Biomedical Campus; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
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T
Polvikoski
Institute of Genetic Medicine (D.J.L.-S., J.D., A.P., H.G., R.H., P.F.C.), Institute of Neuroscience (T.P.), Newcastle University; Newcastle upon Tyne Hospitals NHS Foundation Trust (D.J.L.-S., T.P., D.B., R.H.); MRC-Mitochondrial Biology Unit (P.F.C.), Cambridge Biomedical Campus; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
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D
Birchall
Institute of Genetic Medicine (D.J.L.-S., J.D., A.P., H.G., R.H., P.F.C.), Institute of Neuroscience (T.P.), Newcastle University; Newcastle upon Tyne Hospitals NHS Foundation Trust (D.J.L.-S., T.P., D.B., R.H.); MRC-Mitochondrial Biology Unit (P.F.C.), Cambridge Biomedical Campus; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
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R
Horvath
Institute of Genetic Medicine (D.J.L.-S., J.D., A.P., H.G., R.H., P.F.C.), Institute of Neuroscience (T.P.), Newcastle University; Newcastle upon Tyne Hospitals NHS Foundation Trust (D.J.L.-S., T.P., D.B., R.H.); MRC-Mitochondrial Biology Unit (P.F.C.), Cambridge Biomedical Campus; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
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PF
Chinnery