Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice

Author:

Sun Bo1ORCID,Rouzbehani Omid M.T.2,Kramer Ryan J.1,Ghosh Rajeshwary2,Perelli Robin M.3,Atkins Sage1,Fatahian Amir Nima2ORCID,Davis Kathryn4,Szulik Marta W.4ORCID,Goodman Michael A.2,Hathaway Marissa A.2,Chi Ellenor2,Word Tarah A.5,Tunuguntla Hari6ORCID,Denfield Susan W.6,Wehrens Xander H.T.567,Whitehead Kevin J.8,Abdelnasser Hala Y.9,Warren Junco S.410,Wu Mingfu9ORCID,Franklin Sarah4ORCID,Boudina Sihem2ORCID,Landstrom Andrew P.13ORCID

Affiliation:

1. Department of Pediatrics, Division of Cardiology (B.S., R.J.K., S.A., A.P.L.), Duke University School of Medicine, Durham, NC.

2. Department of Nutrition and Integrative Physiology, Program in Molecular Medicine (O.M.T.R., R.G., A.N.F., M.A.G., M.A.H., E.C., S.B.), University of Utah, Salt Lake City.

3. Department of Cell Biology (R.M.P., A.P.L.), Duke University School of Medicine, Durham, NC.

4. Nora Eccles Harrison Cardiovascular Research and Training Institute (K.D., M.W.S., J.S.W., S.F.), University of Utah, Salt Lake City.

5. Department of Molecular Physiology and Biophysics (T.A.W., X.H.T.W.), Baylor College of Medicine, Houston, TX.

6. Department of Medicine and Pediatrics, Section of Cardiology (H.T., S.W.D., X.H.T.W.), Baylor College of Medicine, Houston, TX.

7. Department of Neuroscience, Cardiovascular Research Institute, and Center for Space Medicine (X.H.T.W.), Baylor College of Medicine, Houston, TX.

8. Division of Cardiovascular Medicine, Department of Internal Medicine (K.J.W.), University of Utah School of Medicine, Salt Lake City.

9. Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, TX (H.Y.A., M.W.).

10. Division of Cardiovascular Medicine (J.S.W.), University of Utah School of Medicine, Salt Lake City.

Abstract

BACKGROUND: PRDM16 plays a role in myocardial development through TGF-β (transforming growth factor-beta) signaling. Recent evidence suggests that loss of PRDM16 expression is associated with cardiomyopathy development in mice, although its role in human cardiomyopathy development is unclear. This study aims to determine the impact of PRDM16 loss-of-function variants on cardiomyopathy in humans. METHODS: Individuals with PRDM16 variants were identified and consented. Induced pluripotent stem cell–derived cardiomyocytes were generated from a proband hosting a Q187X nonsense variant as an in vitro model and underwent proliferative and transcriptional analyses. CRISPR (clustered regularly interspaced short palindromic repeats)-mediated knock-in mouse model hosting the Prdm16 Q187X allele was generated and subjected to ECG, histological, and transcriptional analysis. RESULTS: We report 2 probands with loss-of-function PRDM16 variants and pediatric left ventricular noncompaction cardiomyopathy. One proband hosts a PRDM16-Q187X variant with left ventricular noncompaction cardiomyopathy and demonstrated infant-onset heart failure, which was selected for further study. Induced pluripotent stem cell-derived cardiomyocytes prepared from the PRDM16-Q187X proband demonstrated a statistically significant impairment in myocyte proliferation and increased apoptosis associated with transcriptional dysregulation of genes implicated in cardiac maturation, including TGF-β–associated transcripts. Homozygous Prdm16 Q187X/Q187X mice demonstrated an underdeveloped compact myocardium and were embryonically lethal. Heterozygous Prdm16 Q187X/WT mice demonstrated significantly smaller ventricular dimensions, heightened fibrosis, and age-dependent loss of TGF-β expression. Mechanistic studies were undertaken in H9c2 cardiomyoblasts to show that PRDM16 binds TGFB3 promoter and represses its transcription. CONCLUSIONS: Novel loss-of-function PRDM16 variant impairs myocardial development resulting in noncompaction cardiomyopathy in humans and mice associated with altered TGF-β signaling.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3