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Neurology Genetics
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December 2016; 2 (6) ArticleOpen Access

Novel HSPB1 mutation causes both motor neuronopathy and distal myopathy

D.J. Lewis-Smith, J. Duff, A. Pyle, H. Griffin, T. Polvikoski, D. Birchall, R. Horvath, P.F. Chinnery
First published October 31, 2016, DOI: https://doi.org/10.1212/NXG.0000000000000110
D.J. Lewis-Smith
From the 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
From the 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
From the 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
From the 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
From the 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
From the 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
From the 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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P.F. Chinnery
From the 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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Citation
Novel HSPB1 mutation causes both motor neuronopathy and distal myopathy
D.J. Lewis-Smith, J. Duff, A. Pyle, H. Griffin, T. Polvikoski, D. Birchall, R. Horvath, P.F. Chinnery
Neurol Genet Dec 2016, 2 (6) e110; DOI: 10.1212/NXG.0000000000000110

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    Figure 1 Pedigree, MRI, and muscle histology

    (A) Pedigree of a family of Irish descent with evidence of distal neuromuscular disease in I-1, III-1, III-3, and III-5. *DNA was available for Sanger sequencing, **DNA was available for whole-exome and Sanger sequencing. (B) T1 MRI of III-1 demonstrating severe fatty replacement of the muscles of the lower leg with relative sparing of tibialis anterior (green arrows). (C) Less marked fatty replacement and (D) active high short tau inversion recovery signal abnormality of the muscles of the lower thigh, principally affecting biceps femoris and semimembranosus (red arrowheads) but also the vasti, with relative sparing of sartorius and semitendinosus, and complete sparing of the adductors, rectus femoris, and gracilis (green arrows). (E) Minor T1 changes in the upper thigh. Muscle histology of gastrocnemius (III-1) (F–I) and of tibialis anterior (III-5) (J–P). (F) Hematoxylin & eosin (HE) staining demonstrating a wide range of fiber diameters and groups of small fibers, internal nucleation (G), and an increase in endomysial and perimysial fibrous connective tissue. (H) Scattered fibers contain vacuoles without a basophilic rim. Few fibers show acute necrosis or phagocytosis, but there is a small mononuclear cell inflammatory focus around a blood vessel (I). (J) HE staining demonstrating variation in fiber size with round atrophic fibers (K) and a slightly increased frequency of muscle fibers with internal nuclei (L). (M) Oxidative staining with NADH shows mildly moth-eaten fibers and mild subsarcolemmal accentuation in ring-shaped fibers. (N and O) Esterase histochemistry within the inset demonstrates angulated and rounded atrophic fibers with intense esterase staining and internal nuclei. (P) Adenosine triphosphatase (pH 4.3) staining demonstrating fiber-type grouping and some angulated fibers. Gastrocnemius is recognized to be more prone to secondary myopathic change than tibialis anterior. The following antibodies were used for muscle histochemistry: dystrophin: Dy10/12B2 (N term), Dy4/6 D3 (rod), and Dy8/6C5 (C term); associated glycoproteins: Ad1/20A6 (α-sarcoglycan), βSarc1/5B1 (β-sarcoglycan), 35DAG/21B5 (γ-sarcoglycan), δSarc3/12C1 (δ-sarcoglycan), and 43DAG/8D5 (β-dystroglycan); β-spectrin: RBC2/3D5 (to monitor membrane integrity on sections); laminins: commercial anti–laminin α5 (Chemicon MAB 1924), β1 (Chemicon MAB 1921) and γ1 chain (Chemicon MAB 1920), and Mer3/22B2 (equivalent to 300 kDa α2 chain fragment); caveolin 3, Emerin, and lamin A/C: commercial antibodies (Transduction Labs C38320 and Novocastra NCL-LAM-A/C, respectively); calpain 3: Calp3d/2C4 (exon 1) and Calp3c/12A2 (exon 8); dysferlin: NCL-hamlet (exon 53) and Ham3/17B2 (at exon 11-12 junction); and telethonin (G-11), neonatal myosin heavy chain (NCL-MHCn).

  • Figure 2
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    Figure 2 Sequence validation, functional conservation, and Western blot data

    (A) Sanger sequencing electropherograms demonstrating the segregation of the heterozygous HSPB1 c.387C>G variant with the disease phenotype in the 4 siblings. (B) Correspondence of the novel pathologic α-crystallin domain mutation site (in red) in human HSPB1 to human CRYAB and HSPB1 analogs in other species. Sites of known pathologic mutations are in blue. (C) Western blot of HSPB1 and CRYAB expression in control (F152, F153, and F011) and patient-derived fibroblasts before, and immediately after, heat shock by 1-hour incubation at 44°C.

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