A missense mutation in the αB-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.

AβPP-overexpression and proteasome inhibition increase αB-crystallin in cultured human muscle: Relevance to inclusion-body myositis

“…Our studies of cultured human muscle fibers bearing the transthyretin Val122Ile mutation and overexpressing AβPP indicated that increased muscle fiber degeneration is associated with increased Aβ oligomerization [11]. Of interest is a recent study related to cultured cardiomyocytes which experimentally expressed both αBC bearing the R120G mutation, causing desmin-related myopathy [30], and a toxic amyloidogenic peptide PQ81 [31]. Those cardiomyocytes had pronounced aggresome formation but, interestingly, inhibition of the aggresome formation through additional expression of the wild αBC led to increased accumulation of PQ81 amyloidoligomers and increased cellular toxicity [31].…”

Proteostasis in cardiac health and disease

“…HSPB5 and HSPB7 are normally enriched at sarcomeres at the Z disk and are essential for actin anchoring, indicating a primary role in con trolling sarcomere homeostasis. Cardiomyocytes with a CRYAB R120G mutation have an irregular sarcomeric struc ture and defective chaperone like function, which can trigger desmin related myopathy and early onset cardio myopathy 90,91 . Whether the effect of the mutation results from gain of toxic function or loss of function of the wild type protein or protein complex remains unknown.…”

Variations in the abundance of 24 protein biomarkers of beef tenderness according to muscle and animal type

“…These three proteins are present in great abundance in muscle tissue. According to Vicart et al (1998), their high expression level would allow them to exert an intermediate protective effect in response to stress conditions with no lag time necessary for protein synthesis. They constitute a dynamic complex (Sun and MacRae, 2005).…”