Zhiqun Zhou, PhD
Molecular mechanisms underlying malignant MYL2 mutations leading to cardiac and slow skeletal muscle myopathies. Supported by AHA 15POST25080302 (07/01/2015-06/30/2017)
Cardioskeletal myopathy with onset and death in infancy, morphological features of muscle type I hypotrophy with myofibrillar disorganization and hypertrophic/dilated cardiomyopathy were previously reported in three Dutch families. Recently, Weterman et al. identified the genetic cause of this disorder to be related to the MYL2 gene encoding the ventricular myosin RLC and slow-twitch skeletal muscle RLC. The homozygous splice site mutation IVS6-1 (c403-1G>C) was detected in the last acceptor splice site of MYL2 and, for the first time, it was linked to the fiber type I hypotrophy with myofibrillar disarray and hypertrophic or dilated cardiomyopathy. Interestingly, the same IVS6-1 splice site mutation was earlier identified together with the K104E mutation of RLC, identified in a Danish proband with pronounced septal hypertrophy. One family member carrying only IVS6-1 had pronounced proximal septal hypertrophy, while two other family members exclusively carrying the K104E mutation have not manifested clinical phenotypes consistent with HCM. The molecular mechanisms and functional consequences of this novel RLC IVS6-1 mutation have not been investigated before. This proposal focus on identifying and characterizing, for the first time, the structural and functional effects and molecular mechanisms of this newly IVS6-1-induced cardiac disease with the ultimate goal to find potential rescue strategies to alleviate or prevent the mutation-induced cardiac dysfunction.