Abstract 736: Left Ventricular Noncompaction Associated With Mutations in Cardiac Na Channel Gene SCN5A
Left ventricular noncompaction (LVNC) is newly classified as a primary cardiomyopathy characterized by spongy morphological appearance of left ventricle (LV), and is attributable to intrauterine arrest of endomyocardial development. Although several responsible genes have been reported in LVNC, its precise pathogenesis remains to be elucidated. Most recently, a heterozygous Scn5a knockout mice study demonstrated that monogenic ion channel defect can progressively lead to myocardial structural anomalies. In order to assess the hypothesis that ion channel defect may be involved in the pathogenesis of LVNC, we genetically screened two families with LVNC originally diagnosed as congenital sick sinus syndrome (SSS) and long QT syndrome (LQTS). The proband of the SSS kindred had episodes of bradycardia and a family history of sudden death, and there is a family history of syncope in the LQTS kindred. Genetic screening revealed SCN5A mutations R219H and E1784K in the SSS and LQTS kindreds, respectively. Two dimensional echocardiography revealed heavy trabeculation of the apical half of LV exclusively in the SCN5A mutation carriers of both kindreds. There were no co-existing structural abnormalities. When heterologously expressed in tsA-201cells, R219H channel was non-functional, probably because the mutation is located at the segment S4, a putative activation gate of the Na channel. E1784K channel exhibited persistent late current, a characteristic of type-3 LQTS, but it also showed prominent loss-of-function properties with large hyperpolarizing shift of inactivation (−14.7 mV), depolarizing shift of activation (+11.6 mV), significantly faster current decay (tauslow at −20 mV: wild type=3.53±0.23 ms, n=23; E1784K=1.97±0.14 ms, n=13), and smaller peak current. Mutations in SCN5A are responsible for hereditary ion channelopathies which usually manifest during neonatal or postnatal periods, however, they may potentially affect the channel functions during development. In conclusion, cosegregation of LVNC and SCN5A mutations in our study suggest that defect of SCN5A may disrupt the channel interfaces and architecture with other proteins during development, thereby leading to myocardial structural abnormalities as is observed in LVNC.