本期文章：《自然—遗传学》：Online/在线发表

加拿大蒙特利尔大学Gregor Andelfinger研究小组取得一项新进展，他们近期研究发现了ADAMTS19基因的丢失导致进展性非综合征性心脏瓣膜疾病。相关论文2019年12月16日在线发表于国际学术期刊《自然—遗传学》。

研究人员表示，约有2％的人患有瓣膜性心脏病。尽管最初的观察通常位于局部（例如主动脉瓣或二尖瓣），但在其他瓣膜中定期观察到疾病表现，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，仅有少数基因被确定为该疾病的单基因病因。

研究人员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，他们在生命的早期就出现了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中的纯合子均被截断成了无意义的等位基因。Adamts19的纯合基因敲除小鼠显示主动脉瓣功能障碍，概括了人类表型的各个方面。使用lacZ报告基因和单细胞RNA测序进行的表达分析突出了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论将Adamts19置于Wnt信号通路下游的转录因子淋巴增强剂结合因子1驱动的高度区分性网络中。在Adamts19基因敲除小鼠中，心内膜Krüppel样因子2的上调先于血液动力改变，表明Wnt–Adamts19–Klf2信号轴上的紧密平衡对于适当的瓣膜成熟和维持是必需的。

附：英文原文

Title: Loss of ADAMTS19 causes progressive non-syndromic heart valve disease

Author: Florian Wnnemann, Asaf Ta-Shma, Christoph Preuss, Severine Leclerc, Patrick Piet van Vliet, Andrea Oneglia, Maryse Thibeault, Emily Nordquist, Joy Lincoln, Franka Scharfenberg, Christoph Becker-Pauly, Philipp Hofmann, Kirstin Hoff, Enrique Audain, Hans-Heiner Kramer, Wojciech Makalowski, Amiram Nir, Sebastian S. Gerety, Matthew Hurles, Johanna Comes, Anne Fournier, Hanna Osinska, Jeffrey Robins, Michel Pucat, Orly Elpeleg, Marc-Phillip Hitz, Gregor Andelfinger

Issue&Volume: 2019-12-16

Abstract: 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 disease2,3,4,5,6,7. 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.

DOI: 10.1038/s41588-019-0536-2

Source: https://www.nature.com/articles/s41588-019-0536-2

期刊信息

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：25.455
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex