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A missense mutation in the αB-crystallin chaperone gene causes a desmin-related myopathy

Nature Genetics volume 20, pages 92–95 (1998)Cite this article

Abstract

Desmin-related myopathies (DRM) are inherited neuromuscular disorders characterized by adult onset and delayed accumulation of aggregates of desmin, a protein belonging to the type III intermediate filament family, in the sarcoplasma of skeletal and cardiac muscles1,2. In this paper, we have mapped the locus for DRM in a large French pedigree to a 26-cM interval in chromosome 11q21–23. This region contains the αB-crystallin gene (CRYAB), a candidate gene encoding a 20-kD protein that is abundant in lens and is also present in a number of non-ocular tissues, including cardiac and skeletal muscle3,4. αB-crystallin is a member of the small heat shock protein (shsp) family and possesses molecular chaperone activity5. We identified an R120G missense mutation in CRYAB that co-segregates with the disease phenotype in this family. Muscle cell lines transfected with the mutant CRYAB cDNA showed intracellular aggregates that contain both desmin and αB-crystallin as observed in muscle fibers from DRM patients. These results are the first to identify a defect in a molecular chaperone as a cause for an inherited human muscle disorder.

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Figure 1: Pedigree and genotypic analysis of a DRM family.
Figure 2: Transverse cryostat sections of the muscle from a DRM patient (III8 on pedigree).
Figure 3: Cytoplasmic aggregates are formed in desmin-containing cells transfected with R120G αB-crystallin cDNA.
Figure 4: Ultrastructural analysis of aggregates in BHK21 cells transfected with R120G αB-crystallin cDNA.

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Acknowledgements

We thank the family members for their help with this study. We also acknowledge R. Hellio for assistance with confocal microscopy. We thank M.M. Portier, G. Butler-Browne and R. Krishnamoorthy for helpful discussion. This work was supported by Association Française contre les Myopathies and Ministère de l’Education Nationale, de l'Enseignement Supérieur et de la Recherche.

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Author notes

  1. Jean-Marie Dupret: INSERM U 458, Hôpital Robert Debré, 75019 Paris, France. The first two authors contributed equally to this work.

Authors and Affiliations

  1. Institut Pasteur, 25 rue du Dr Roux, Paris, 75015, France

    Patrick Vicart, Zhenlin Li, Marie-Christine Prévost & Denise Paulin

  2. UFR de Biochimie, Université Paris VII, 2 place Jussieu, Paris, 75005, France

    Patrick Vicart, Zhenlin Li, Jean-Marie Dupret & Denise Paulin

  3. INSERM U 153, Institut de Myologie, Groupe Hospitalier Pitié-Salpétrière, Paris, 75013, France

    Anne Caron, Pascale Guicheney, Danielle Chateau, Fernando Tomé & Michel Fardeau

  4. Généthon, 1 rue de l’Internationale, Evry, 91002, France

    Armelle Faure

  5. Laboratoire de Neuropathologie, CHU Côte de Nacre, Caen, 14033, France

    Françoise Chapon

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  1. Patrick Vicart
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Correspondence to Patrick Vicart.

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Vicart, P., Caron, A., Guicheney, P. et al. A missense mutation in the αB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet 20, 92–95 (1998). https://doi.org/10.1038/1765

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