Department of Genetics (H.N.D., R.C., M.S., E.A.A.), Stanford University, CA.
Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA.
Circ Genom Precis Med. 2022 Aug;15(4):e003563. doi: 10.1161/CIRCGEN.121.003563. Epub 2022 Jun 7.
The study of hypertrophic cardiomyopathy (HCM) can yield insight into the mechanisms underlying the complex trait of cardiac hypertrophy. To date, most genetic variants associated with HCM have been found in sarcomeric genes. Here, we describe a novel HCM-associated variant in the noncanonical Wnt signaling interactor (Wilms tumor interacting protein) and provide evidence of a role for WTIP in complex disease.
In a family affected by HCM, we used exome sequencing and identity-by-descent analysis to identify a novel variant in WTIP (p.Y233F). We knocked down WTIP in isolated neonatal rat ventricular myocytes with lentivirally delivered short hairpin ribonucleic acids and in via morpholino injection. We performed weighted gene coexpression network analysis for WTIP in human cardiac tissue, as well as association analysis for WTIP variation and left ventricular hypertrophy. Finally, we generated induced pluripotent stem cell-derived cardiomyocytes from patient tissue, characterized size and calcium cycling, and determined the effect of verapamil treatment on calcium dynamics.
WTIP knockdown caused hypertrophy in neonatal rat ventricular myocytes and increased cardiac hypertrophy, peak calcium, and resting calcium in . Network analysis of human cardiac tissue indicated WTIP as a central coordinator of prohypertrophic networks, while common variation at the locus was associated with human left ventricular hypertrophy. Patient-derived p.Y233F-induced pluripotent stem cell-derived cardiomyocytes recapitulated cellular hypertrophy and increased resting calcium, which was ameliorated by verapamil.
We demonstrate that a novel genetic variant found in a family with HCM disrupts binding to a known Wnt signaling protein, misregulating cardiomyocyte calcium dynamics. Further, in orthogonal model systems, we show that expression of the gene is important in complex cardiac hypertrophy phenotypes. These findings, derived from the observation of a rare Mendelian disease variant, uncover a novel disease mechanism with implications across diverse forms of cardiac hypertrophy.
肥厚型心肌病（HCM）的研究可以深入了解心脏肥大这一复杂特征的潜在机制。迄今为止，大多数与 HCM 相关的遗传变异都在肌节基因中发现。在这里，我们描述了一个非典型 Wnt 信号相互作用物（Wilms 肿瘤相互作用蛋白）与 HCM 相关的新变异，并提供了 WTIP 在复杂疾病中发挥作用的证据。
在一个受 HCM 影响的家族中，我们使用外显子组测序和身份相依分析来鉴定 WTIP 中的一个新变异（p.Y233F）。我们使用慢病毒传递短发夹 RNA 敲低 WTIP 在分离的新生大鼠心室肌细胞中，以及通过形态发生素注射在 中敲低 WTIP。我们对人类心脏组织中的 WTIP 进行加权基因共表达网络分析，以及 WTIP 变异与左心室肥大的关联分析。最后，我们从患者组织中生成诱导多能干细胞衍生的心肌细胞，表征大小和钙循环，并确定维拉帕米治疗对钙动力学的影响。
WTIP 敲低导致新生大鼠心室肌细胞肥大，并增加 中的心脏肥大、峰值钙和静息钙。人类心脏组织的网络分析表明，WTIP 是促肥大网络的中央协调者，而 基因座的常见变异与人类左心室肥大有关。患者衍生的 p.Y233F 诱导多能干细胞衍生的心肌细胞重现了细胞肥大和静息钙增加，维拉帕米可改善这一现象。
我们证明，在一个 HCM 家族中发现的一个新的遗传变异会破坏与已知的 Wnt 信号蛋白的结合，从而使心肌细胞钙动力学失调。此外，在正交模型系统中，我们表明该基因的表达在复杂的心脏肥大表型中很重要。这些发现源自对一种罕见的孟德尔疾病变异的观察，揭示了一种新的疾病机制，对多种形式的心脏肥大具有重要意义。
