Valvular heart disease is observed in approximately 2% of the general population1. Although the initial observation is often localized (for example, to the aortic or mitral valve), disease manifestations are regularly observed in the other valves and patients frequently require surgery. Despite the high frequency of heart valve disease, only a handful of genes have so far been identified as the monogenic causes of disease2-7. Here we identify two consanguineous families, each with two affected family members presenting with progressive heart valve disease early in life. Whole-exome sequencing revealed homozygous, truncating nonsense alleles in ADAMTS19 in all four affected individuals. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype. Expression analysis using a lacZ reporter and single-cell RNA sequencing highlight Adamts19 as a novel marker for valvular interstitial cells; inference of gene regulatory networks in valvular interstitial cells positions Adamts19 in a highly discriminatory network driven by the transcription factor lymphoid enhancer-binding factor 1 downstream of the Wnt signaling pathway. Upregulation of endocardial Krüppel-like factor 2 in Adamts19 knockout mice precedes hemodynamic perturbation, showing that a tight balance in the Wnt-Adamts19-Klf2 axis is required for proper valve maturation and maintenance.

中文翻译：

---

ADAMTS19 的缺失导致进行性非综合征性心脏瓣膜病。

在大约 2% 的普通人群中观察到心脏瓣膜病1。虽然最初的观察通常是局部的（例如，主动脉瓣或二尖瓣），但在其他瓣膜中经常观察到疾病表现，并且患者经常需要手术。尽管心脏瓣膜疾病的发病率很高，但迄今为止只有少数基因被确定为疾病的单基因原因2-7。在这里，我们确定了两个近亲家庭，每个家庭都有两个受影响的家庭成员在生命早期出现进行性心脏瓣膜病。全外显子组测序在所有四个受影响的个体中揭示了 ADAMTS19 中纯合的、截断的无意义等位基因。Adamts19 的纯合基因敲除小鼠表现出主动脉瓣功能障碍，概括了人类表型的各个方面。使用 lacZ 报告基因和单细胞 RNA 测序的表达分析突出了 Adamts19 作为瓣膜间质细胞的新标记；瓣膜间质细胞中基因调控网络的推断将 Adamts19 定位在由 Wnt 信号通路下游的转录因子淋巴增强子结合因子 1 驱动的高度区分网络中。Adamts19 敲除小鼠心内膜 Krüppel 样因子 2 的上调先于血流动力学扰动，这表明 Wnt-Adamts19-Klf2 轴的紧密平衡对于瓣膜的适当成熟和维持是必需的。瓣膜间质细胞中基因调控网络的推断将 Adamts19 定位在由 Wnt 信号通路下游的转录因子淋巴增强子结合因子 1 驱动的高度区分网络中。Adamts19 敲除小鼠心内膜 Krüppel 样因子 2 的上调先于血流动力学扰动，这表明 Wnt-Adamts19-Klf2 轴的紧密平衡对于瓣膜的适当成熟和维持是必需的。瓣膜间质细胞中基因调控网络的推断将 Adamts19 定位在由 Wnt 信号通路下游的转录因子淋巴增强子结合因子 1 驱动的高度区分网络中。Adamts19 敲除小鼠心内膜 Krüppel 样因子 2 的上调先于血流动力学扰动，这表明 Wnt-Adamts19-Klf2 轴的紧密平衡对于瓣膜的适当成熟和维持是必需的。