A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy.
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.
Vicart
P
P
Institut Pasteur, Paris, France. pvicart@pasteur.fr
Caron
A
A
Guicheney
P
P
Li
Z
Z
Prévost
M C
MC
Faure
A
A
Chateau
D
D
Chapon
F
F
Tomé
F
F
Dupret
J M
JM
Paulin
D
D
Fardeau
M
M
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
D003459:Crystallins; D003893:Desmin; D005819:Genetic Markers; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011994:Recombinant Proteins