Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, SA MRC Centre for Tuberculosis Research, Stellenbosch University, P.O. Box 19063, Tygerberg, 7505, South Africa.
Department of Statistics, Faculty of Natural Sciences, University of the Western Cape, Cape Town, South Africa.
Hum Genet. 2016 May;135(5):477-483. doi: 10.1007/s00439-016-1649-7. Epub 2016 Mar 11.
Left ventricular hypertrophy is a risk factor for cardiovascular morbidity and mortality. Hypertrophic cardiomyopathy (HCM) is considered a model disease to study causal molecular factors underlying isolated cardiac hypertrophy. However, HCM manifests with various clinical symptoms, even in families bearing the same genetic defects, suggesting that additional factors contribute to hypertrophy. The gene encoding the cardiac myosin binding protein C (cMYBPC) is one of the most frequently implicated genes in HCM. Recently another myosin binding protein, myosin binding protein H (MYBPH) was shown to function in concert with cMYBPC in regulating cardiomyocyte contraction. Given the similarity in sequence, structure and the critical role MYBPH plays in sarcomere contraction, we proposed that MYBPH may be involved in HCM pathogenesis. Family-based genetic association analysis was employed to investigate the contribution of MYBPH in modifying hypertrophy. Seven single nucleotide polymorphisms and haplotypes in MYBPH were investigated for hypertrophy modifying effects in 388 individuals (27 families), in which three unique South African HCM-causing founder mutations (p.R403W and pA797T in β-myosin heavy chain gene (MYH7) and p.R92W in the cardiac troponin T gene (TNNT2)) segregate. We observed a significant association between rs2250509 and hypertrophy traits in the p.A797T MYH7 mutation group. Additionally, haplotype GGTACTT significantly affected hypertrophy within the same mutation group. MYBPH was for the first time assessed as a candidate hypertrophy modifying gene. We identified a novel association between MYBPH and hypertrophy traits in HCM patients carrying the p.A797T MYH7 mutation, suggesting that variation in MYBPH can modulate the severity of hypertrophy in HCM.
左心室肥厚是心血管发病率和死亡率的一个危险因素。肥厚型心肌病（HCM）被认为是研究孤立性心肌肥厚潜在因果分子因素的模型疾病。然而，HCM 表现出各种临床症状，即使在携带相同遗传缺陷的家族中也是如此，这表明还有其他因素导致肥厚。编码心肌肌球蛋白结合蛋白 C（cMYBPC）的基因是 HCM 中最常涉及的基因之一。最近，另一种肌球蛋白结合蛋白肌球蛋白结合蛋白 H（MYBPH）被证明与 cMYBPC 协同作用，调节心肌细胞收缩。鉴于 MYBPH 在序列、结构上的相似性以及在肌节收缩中发挥的关键作用，我们提出 MYBPH 可能参与 HCM 的发病机制。采用基于家族的遗传关联分析来研究 MYBPH 在修饰肥厚方面的作用。在 388 个人（27 个家庭）中，研究了 MYBPH 中的 7 个单核苷酸多态性和单倍型对肥厚的修饰作用，其中 3 个独特的南非 HCM 致病基因突变（β-肌球蛋白重链基因（MYH7）中的 p.R403W 和 pA797T 以及心脏肌钙蛋白 T 基因（TNNT2）中的 p.R92W）分离。我们观察到 rs2250509 与携带 p.A797T MYH7 突变的个体的肥厚表型之间存在显著相关性。此外，在同一突变组内，GGTACTT 单倍型显著影响肥厚。MYBPH 首次被评估为候选肥厚修饰基因。我们在携带 p.A797T MYH7 突变的 HCM 患者中发现了 MYBPH 与肥厚表型之间的新关联，表明 MYBPH 的变异可以调节 HCM 中肥厚的严重程度。
