Abstract 915: A Novel Missense Mutation in Cardiac Ryanodine Receptor Gene as a Possible Cause of Hypertrophic Cardiomyopathy: Evidence From Familial Analysis
Background: The sarcoplasmic reticulum (SR) is an intracellular membranous network, which plays an essential role in mediating contraction and relaxation in the cardiomyocyte. Cardiac ryanodine receptor (cRyR) is one of the major regulators of the SR, and previous studies demonstrated that mutations in cRyR gene with abnormalities in SR calcium might also cause hypertrophic cardiomyopathy (HCM) in experimental mouse model. We therefore hypothesized that mutations in cRyR gene could cause HCM in human. Methods and Results: First we screened for mutations in all 8 sarcomere genes in 300 probands with HCM by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). After detecting and excluding all sarcomere gene mutation carriers from these probands, we screened for cRyR gene mutations in the remaining 187 probands with HCM by PCR-SSCP and identified a novel missense mutation Thr1107Met in a proband who demonstrated left ventricular outflow tract obstruction (80 mmHg of pressure gradient) with a history of ventricular fibrillation. The further family study of the proband revealed 4 mutation carriers (age 41.0 +/− 13.6). All carriers showed asymmetric septal hypertrophy with 21.0 +/− 5.9 mm and normal thickness of posterior wall with 11.3 +/− 2.3 mm. Under these conditions, left ventricular end-diastolic dimension (41.8 +/− 4.4 mm) and %fractional shortening (44.5 +/− 5.6) were normal. Right ventricles were normal in size and function in all of the subjects and denied the diagnosis of arrhythmogenic right ventricular dysplasia. The analysis of the genomic DNA of all available individuals from the family indicated that the cRyR Thr1107Met mutation inherited in this pedigree and suggested that this mutation caused disease, because it cosegregated with the affected status. Furthermore, cRyR-Thr1107Met was absent in the other 299 probands or 200 normal controls. Conclusions: The present study demonstrates a novel missense mutation Thr1107Met in cRyR gene which can cause HCM in human. The degree of hypertrophy is moderate and the disease penetrance with the mutation is high in the pedigree (100%). We suggest new insights into pathogenic mechanisms whereby mutations in calcium-related gene lead to hypertrophic remodeling in HCM.