Abstract 2728: Read-Through Mutation in αB-Crystallin Associated with Congenital Posterior Pole Cataract and Adult Onset Dilating Cardiomyopathy. A New Phenotype.
Introduction: αB-crystallin (CRYAB) encodes a protein that is a structural component of the lens of the eye and serves as a molecular chaperone in skeletal and heart muscle. Mutations in CRYAB have been reported in desmin related myopathies, with and without hypertrophic cardiomyopathy. Mutations in the same gene have been documented in two large multi-generation families with autosomal dominant congenital posterior pole cataract (CPPC) without cardiomyopathy. Finally, a missense mutation has been reported in a single Japanese patient with late onset familial dilated cardiomyopathy (DCM).
Case report: a family was ascertained in which 4 individuals in 2 generations had a combination of congenital cataract and adult onset cardiomyopathy. Three of them had died prior to this study. The index patient, a 41 year old woman, suffered from CPPC and DCM. No evidence for a skeletal myopathy was found. Using a candidate gene approach an unusual read-through mutation in CRYAB was found, abolishing the stop-codon and leading to the extension of the normal αB-crystallin protein with nineteen residues. This mutation was also present in her two sons with CPPC, but absent in her healthy daughter. In the sons discrete repolarisation abnormalities could be demonstrated, that probably precede the onset of cardiomyopathy.
Discussion: a new phenotype is described, combining CPPC with adult onset DCM, thereby expanding the disease spectrum of αB-crystallinopathies. The unusual type of mutation detected in this family will add to our understanding of the mechanisms involved in the causation of cataract and cardiomyopathy in αB-crystallinopahies. Furthermore, the finding of a CRYAB mutation in this family supports the claim that mutations in this gene may be a rare cause of genetically determined DCM.