Abstract 1579: Novel Mutations in the Molecular Chaperone alphaB-Crystallin Cause Cardiomyopathies
Background: αB-crystallin is as a member of the small heat shock protein family and a molecular chaperone expressed in the human heart and skeletal muscles. During cardiac ischemia αB-crystallin translocates from the cytosol to the myofibrils where it binds to desmin and titin filaments and protect these myofibrillar proteins from unfolding or aggregation during stress conditions. Genetic variations in the C-terminus of the αB-crystallin gene CRYAB (R120G) has previously been associated with human Desmin-related myopathy (DRM) and transgenic mice exhibit DRM characterized by aggregation of desmin, abnormal muscular function and heart failure. Other C-terminal mutations 464delCT and Q151X have been associated with myopathy and 450delA, with cataract. Recently, a R157H mutation also situated in the C-terminus was associated with Dilated Cardiomyopathy (DCM).
Methods: We analyzed 90 patients with hypertrophic cardiomyopathy (HCM) and 200 patients with DCM for mutations in CRYAB using single strand polymorphism conformation analysis and subsequently DNA sequencing of aberrant conformers.
Results: Two HCM probands were heterozygous carriers of the N-terminal mutations Q26X and P39L respectively. Q26X results in haploinsufficiency and thus reduced αB-crystallin expression. The Q39P segregated with family disease and changes a fully conserved helix braking proline residue into a leucine causing severe changes in αB-crystallin secondary structure. In the DCM group, one proband was heterozygous for the C-terminal mutation G154S changing a fully conserved glycine into a serine. This mutation is located close to previously identified disease causing mutations in the CRYAB C-terminus and is most likely associated with decreased chaperone activity.
Discussion: This is the first demonstration that defect chaperone function in the heart is associated with HCM and we recommend that the CRYAB gene should bee screened during diagnostic work-up of cardiomyopathies. Furthermore, as αB-crystallin is found in intracellular amyloid aggregates in DRM the pathogenesis of CRYAB associated cardiomyopathies may be associated with toxic filaments of defective sarcomeric or other proteins due to insufficient chaperone activity in cardiomyocytes.