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Multi-system neurological disorder associated with a CRYAB variant

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Abstract

We report a multiplex family with extended multisystem neurological phenotype associated with a CRYAB variant. Two affected siblings were evaluated with whole exome sequencing, muscle biopsy, laser microdissection, and mass spectrometry-based proteomic analysis. Both patients and their mother manifested a combination of early-onset cataracts, cardiomyopathy, cerebellar ataxia, optic atrophy, cognitive impairment, and myopathy. Whole exome sequencing identified a heterozygous c.458C>T variant mapped to the C-terminal extension domain of the Alpha-crystallin B chain, disrupting its function as a molecular chaperone and its ability to suppress protein aggregation. In accordance with the molecular findings, muscle biopsies revealed subsarcolemmal deposits that appeared dark with H&E and trichrome staining were negative for the other routine histochemical staining and for amyloid with the Congo-red stain. Electron microscopy demonstrated that the deposits were composed of numerous parallel fibrils. Laser microdissection and mass spectrometry-based proteomic analysis revealed that the inclusions are almost exclusively composed of crystallized chaperones/heat shock proteins. Moreover,  a structural model suggests that Ser153 could be involved in monomer stabilization, dimer association, and possible binding of partner proteins. We propose that our report potentially expands the complex phenotypic spectrum of alpha B-crystallinopathies with possible effect of a CRYAB variant on the central nervous system.

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Funding

Work in CGB’s lab is provided by intramural funds of NINDS.

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Authors and Affiliations

  1. Department of Neurology, Wolfson Medical Center and Tel Aviv University, Holon, Israel

    Menachem Sadeh

  2. Department of Microbiology and Molecular Genetics, Faculty of Medicine, Institute for Biomedical Research Israel-Canada, Hebrew University, Jerusalem, Israel

    Dolev Rahat & Ora Schueler-Furman

  3. Department of Genetics, Hadassah Medical Organization and Faculty of Medicine, Hebrew University, Jerusalem, Israel

    Vardiella Meiner

  4. Department of Pathology, Genetics, Hadassah Medical Organization and Faculty of Medicine, Hebrew University, Jerusalem, Israel

    Yakov Fellig

  5. Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Tel Aviv University, Tel Aviv, Israel

    Michael Arad

  6. National Institute of Neurological Disorders and Stroke, Neurogenetics Branch, Bethesda, MD, USA

    Ying Hu & Carsten G. Bönnemann

  7. National Institute of Neurological Disorders and Stroke, Proteomics Core Facility, Bethesda, MD, USA

    Yan Li

  8. Department of Neurology, Genetics, Hadassah Medical Organization and Faculty of Medicine, Hebrew University, Jerusalem, Israel

    Alexander Lossos

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  1. Menachem Sadeh
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  2. Dolev Rahat
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  4. Yakov Fellig
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Correspondence to Menachem Sadeh.

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Sadeh, M., Rahat, D., Meiner, V. et al. Multi-system neurological disorder associated with a CRYAB variant. Neurogenetics 22, 117–125 (2021). https://doi.org/10.1007/s10048-021-00640-x

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