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

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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.