title: A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy.
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 muscles. 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 alphaB-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 muscle. AlphaB-crystallin is a member of the small heat shock protein (shsp) family and possesses molecular chaperone activity. 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 alphaB-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.
authors.affiliation: Institut Pasteur, Paris, France. pvicart@pasteur.fr
authors.forename: P
authors.initials: P
authors.lastname: Vicart
authors.forename: A
authors.initials: A
authors.lastname: Caron
authors.forename: P
authors.initials: P
authors.lastname: Guicheney
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.forename: M C
authors.initials: MC
authors.lastname: Prévost
authors.forename: A
authors.initials: A
authors.lastname: Faure
authors.forename: D
authors.initials: D
authors.lastname: Chateau
authors.forename: F
authors.initials: F
authors.lastname: Chapon
authors.forename: F
authors.initials: F
authors.lastname: Tomé
authors.forename: J M
authors.initials: JM
authors.lastname: Dupret
authors.forename: D
authors.initials: D
authors.lastname: Paulin
authors.forename: M
authors.initials: M
authors.lastname: Fardeau
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D006224:Cricetinae; D003459:Crystallins / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure; D003893:Desmin / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D005819:Genetic Markers; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008126:Lod Score; D008297:Male; D016253:Microscopy, Immunoelectron; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D003459:Crystallins; D003893:Desmin; D005819:Genetic Markers; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011994:Recombinant Proteins