Abstract 1625: Mutational Analysis of CRYAB-Encoded Crystallin Alpha-B in Hypertrophic Cardiomyopathy
Background: Mutations in CRYAB-encoded crystallin alpha-B, a molecular chaperone, have been associated with desmin-related cardiomyopathy, dilated cardiomyopathy (DCM), and most recently hypertrophic cardiomyopathy (HCM). This cardiac/skeletal muscle heat shock protein binds to titin and desmin myofilaments during ischemia to prevent stress-induced unfolding or aggregation. We sought to determine the prevalence and spectrum of CRYAB mutations in a large HCM cohort.
Methods: 1025 unrelated patients (61% male, age at diagnosis 49 ± 18 years, maximum left ventricular wall thickness (MLVWT) 22 ± 7 mm, and mean left ventricular outflow tract gradient (MLVOT) 44 ± 44 mmHg) were analyzed for mutations in the 3 translated exons of CRYAB by polymerase chain reaction, denaturing high performance liquid chromatography and direct DNA sequencing. Genotype data was blinded to the phenotype. Fisher’s exact test was used for statistical analysis.
Results: Overall, two CRYAB missense mutations, R11H (arginine, R, to histidine, H) and G154S (glycine, G, to serine, S), were detected in 9/1025 patients (< 1%). The novel N-terminal mutation, R11H, was discovered in a symptomatic male diagnosed at 53 years (MLVWT 25 mm and MLVOT 71 mmHg). R11H involves a residue that is conserved across species and localizes to the hydrophobic chaperone-active domain. R11H was absent in 400 healthy controls. No other mutations in 8 known HCM-susceptibility genes were detected. G154S-CRYAB was reported previously as a DCM-associated mutation. Here, G154S was identified in 8/1025 patients, but in 0/760 controls (p=0.02). Collectively, these 8 patients (4 male) were diagnosed at 43 ± 27 years with MLVWT of 19 ± 1.6 mm and MLVOT of 66 ± 72 mmHg, and half of patients required septal reduction therapies.
Conclusion: Mutations in CRYAB provide a putative pathogenic mechanism for HCM in < 1% of cases. We detected more patients with CRYAB mutations than with actin-HCM, a gene for which commercial HCM genetic testing is available. Moreover, G154S-CRYAB provides the second example of phenotypic plasticity whereby a specific missense mutation appears to confer susceptibility for distinct and seemingly divergent cardiomyopathic phenotypes, DCM and HCM.