New family with HSPB8-associated autosomal dominant rimmed vacuolar myopathy

Sejad Al-Tahan, Lan Weiss, Howard Yu, Sha Tang, Mario Saporta, Anna Vihola, Tahseen Mozaffar, Bjarne Udd, Virginia Kimonis

Research output: Contribution to journalArticle

Abstract

Objective We clinically and molecularly characterize a new family with autosomal dominant rimmed vacuolar myopathy (RVM) caused by mutations in the HSPB8 gene. Methods We performed whole-exome and whole-genome sequencing in the family. Western blot and immunocytochemistry were used to analyze 3 patient fibroblasts, and findings were compared with their age- and sex-matched controls. Results Affected patients have distal and proximal myopathy, with muscle biopsy showing rimmed vacuoles, muscle fiber atrophy, and endomysial fibrosis typical of RVM. Muscle MRI showed severe relatively symmetric multifocal fatty degenerative changes of the lower extremities. We identified a duplication of C at position 515 of the HSPB8 gene (c.515dupC) by whole-genome sequencing, which caused a frameshift with a predicted alternate stop codon p.P173SFS*43 in all affected individuals, resulting in an elongated protein product. Western blot and immunocytochemistry studies revealed reduced expression of heat shock protein beta 8 in patient fibroblasts compared with control fibroblasts, in addition to disrupted autophagy pathology. Conclusions We report a novel family with autosomal dominant RVM caused by the c.515dupC mutation of the HSPB8 gene, causing a translational frameshift that results in an elongated protein. Understanding the mechanism for the RVM pathology caused by mutated chaperone will permit novel targeted strategies to alter the natural history progression. As next-generation sequencing becomes more available, additional myopathic families will be identified with HSPB8 mutations.

Original languageEnglish (US)
Article number349
JournalNeurology: Genetics
Volume5
Issue number4
DOIs
StatePublished - Aug 1 2019

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Fibroblasts
Mutation
Distal Myopathies
Western Blotting
Immunohistochemistry
Genome
Pathology
Genes
Exome
Muscles
Muscular Atrophy
Terminator Codon
Autophagy
Heat-Shock Proteins
Vacuoles
Natural History
Lower Extremity
Proteins
Fibrosis
Biopsy

ASJC Scopus subject areas

  • Clinical Neurology
  • Genetics(clinical)

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New family with HSPB8-associated autosomal dominant rimmed vacuolar myopathy. / Al-Tahan, Sejad; Weiss, Lan; Yu, Howard; Tang, Sha; Saporta, Mario; Vihola, Anna; Mozaffar, Tahseen; Udd, Bjarne; Kimonis, Virginia.

In: Neurology: Genetics, Vol. 5, No. 4, 349, 01.08.2019.

Research output: Contribution to journalArticle

Al-Tahan, S, Weiss, L, Yu, H, Tang, S, Saporta, M, Vihola, A, Mozaffar, T, Udd, B & Kimonis, V 2019, 'New family with HSPB8-associated autosomal dominant rimmed vacuolar myopathy', Neurology: Genetics, vol. 5, no. 4, 349. https://doi.org/10.1212/NXG.0000000000000349
Al-Tahan, Sejad ; Weiss, Lan ; Yu, Howard ; Tang, Sha ; Saporta, Mario ; Vihola, Anna ; Mozaffar, Tahseen ; Udd, Bjarne ; Kimonis, Virginia. / New family with HSPB8-associated autosomal dominant rimmed vacuolar myopathy. In: Neurology: Genetics. 2019 ; Vol. 5, No. 4.
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