Loss of ADAMTS19 causes progressive non-syndromic heart valve disease.
Loss of ADAMTS19 causes progressive non-syndromic heart valve disease.
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ADAMTS19 的缺失会导致进行性非综合征性心脏瓣膜疾病。
DOI：
10.1038/s41588-019-0536-2
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发表时间：
2020
期刊：
影响因子：
30.8
通讯作者：
Audain,E
中科院分区：
文献类型：
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作者：
Wünnemann,Florian;Ta-Shma,Asaf;Preuss,Christoph;Leclerc,Severine;vanVliet,PatrickPiet;Oneglia,Andrea;Thibeault,Maryse;Nordquist,Emily;Lincoln,Joy;Scharfenberg,Franka;Becker-Pauly,Christoph;Hofmann,Philipp;Hoff,Kirstin;Audain,E
心脏瓣膜病约占总人口的2%。虽然最初的观察通常是局部的（例如，在主动脉瓣或二尖瓣），但在其他瓣膜中也经常观察到疾病的表现，患者经常需要手术治疗。尽管心脏瓣膜疾病的频率很高，但迄今为止只有少数基因被确定为疾病的单基因原因，，，，-。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表现为进行性心脏瓣膜疾病。全外显子组测序显示，在所有四个受影响的个体中，adamts19都有纯合的、截断的无义等位基因。adamts19的纯合子敲除小鼠显示主动脉瓣功能障碍，再现了人类表型的各个方面。利用alacZreporter和单细胞RNA测序进行表达分析，发现adamts19是一个新的瓣膜间质细胞标记物；对瓣膜性间质细胞基因调控网络的推断在Wnt信号通路下游转录因子淋巴增强结合因子1驱动的高度歧视性网络中，sadamts19的位置。adamts19基因敲除小鼠心内膜kr<s:1> pel样因子2的上调先于血流动力学扰动，表明Wnt-Adamts19-Klf2轴的紧密平衡是适当的瓣膜成熟和维持所必需的。
Valvular heart disease is observed in approximately 2% of the general population. 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 disease, , , , –. 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 inADAMTS19in all four affected individuals. Homozygous knockout mice forAdamts19show aortic valve dysfunction, recapitulating aspects of the human phenotype. Expression analysis using alacZreporter and single-cell RNA sequencing highlightAdamts19as a novel marker for valvular interstitial cells; inference of gene regulatory networks in valvular interstitial cells positionsAdamts19in 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 inAdamts19knockout mice precedes hemodynamic perturbation, showing that a tight balance in the Wnt–Adamts19–Klf2 axis is required for proper valve maturation and maintenance.