对涉及先天性和结构性心脏疾病以及心肌病的基因进行广泛鉴定。
Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy.
作者信息
Spielmann Nadine, Miller Gregor, Oprea Tudor I, Hsu Chih-Wei, Fobo Gisela, Frishman Goar, Montrone Corinna, Haseli Mashhadi Hamed, Mason Jeremy, Munoz Fuentes Violeta, Leuchtenberger Stefanie, Ruepp Andreas, Wagner Matias, Westphal Dominik S, Wolf Cordula, Görlach Agnes, Sanz-Moreno Adrián, Cho Yi-Li, Teperino Raffaele, Brandmaier Stefan, Sharma Sapna, Galter Isabella Rikarda, Östereicher Manuela A, Zapf Lilly, Mayer-Kuckuk Philipp, Rozman Jan, Teboul Lydia, Bunton-Stasyshyn Rosie K A, Cater Heather, Stewart Michelle, Christou Skevoulla, Westerberg Henrik, Willett Amelia M, Wotton Janine M, Roper Willson B, Christiansen Audrey E, Ward Christopher S, Heaney Jason D, Reynolds Corey L, Prochazka Jan, Bower Lynette, Clary David, Selloum Mohammed, Bou About Ghina, Wendling Olivia, Jacobs Hugues, Leblanc Sophie, Meziane Hamid, Sorg Tania, Audain Enrique, Gilly Arthur, Rayner Nigel W, Hitz Marc-Phillip, Zeggini Eleftheria, Wolf Eckhard, Sedlacek Radislav, Murray Steven A, Svenson Karen L, Braun Robert E, White Jaqueline K, Kelsey Lois, Gao Xiang, Shiroishi Toshihiko, Xu Ying, Seong Je Kyung, Mammano Fabio, Tocchini-Valentini Glauco P, Beaudet Arthur L, Meehan Terrence F, Parkinson Helen, Smedley Damian, Mallon Ann-Marie, Wells Sara E, Grallert Harald, Wurst Wolfgang, Marschall Susan, Fuchs Helmut, Brown Steve D M, Flenniken Ann M, Nutter Lauryl M J, McKerlie Colin, Herault Yann, Lloyd K C Kent, Dickinson Mary E, Gailus-Durner Valerie, Hrabe de Angelis Martin
机构信息
Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Center Munich (GmbH), German Research Center for Environmental Health, Neuherberg, Germany.
Department of Internal Medicine, Division of Translational Informatics and Center of Biomedical Research Excellence in Autophagy, Inflammation, and Metabolism, UNM Health Sciences Center and UNM Comprehensive Cancer Center, Albuquerque, NM, USA.
出版信息
Nat Cardiovasc Res. 2022 Feb;1(2):157-173. doi: 10.1038/s44161-022-00018-8. Epub 2022 Feb 17.
Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease.
先天性心脏病的临床表现具有异质性，这使得确定致病基因及其遗传途径和作用机制具有挑战性。通过使用体内心电图、经胸超声心动图和微型计算机断层扫描成像技术，对3894个单基因敲除小鼠品系进行心脏结构和功能异常筛查，我们在此识别出705个出现心律失常、心肌肥大和/或心室扩张的品系。在这705个基因中，有486个此前未被发现与人类心脏功能障碍相关，其中一些代表未知相关性的变异（VUR）。Casz1、Dnajc18、Pde4dip、Rnf38或Tmem161b基因发生突变的小鼠表现出发育性心脏结构异常，它们的人类同源基因被归类为VUR。利用英国生物银行的数据，我们通过证明DNAJC18基因功能丧失与左心室收缩功能改变相关，验证了该基因对心脏稳态的重要性。我们的研究结果识别出数百个此前未被认识到的在先天性心脏病中具有潜在功能的基因，并提示了5个VUR在先天性心脏病中的因果作用。
Zotero 插件