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Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-ß Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.
Sun, Bo; Rouzbehani, Omid M T; Kramer, Ryan J; Ghosh, Rajeshwary; Perelli, Robin M; Atkins, Sage; Fatahian, Amir Nima; Davis, Kathryn; Szulik, Marta W; Goodman, Michael A; Hathaway, Marissa A; Chi, Ellenor; Word, Tarah A; Tunuguntla, Hari; Denfield, Susan W; Wehrens, Xander H T; Whitehead, Kevin J; Abdelnasser, Hala Y; Warren, Junco S; Wu, Mingfu; Franklin, Sarah; Boudina, Sihem; Landstrom, Andrew P.
Afiliación
  • Sun B; Department of Pediatrics, Division of Cardiology (B.S., R.J.K., S.A., A.P.L.), Duke University School of Medicine, Durham, NC.
  • Rouzbehani OMT; 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.
  • Kramer RJ; Department of Pediatrics, Division of Cardiology (B.S., R.J.K., S.A., A.P.L.), Duke University School of Medicine, Durham, NC.
  • Ghosh R; 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.
  • Perelli RM; Department of Cell Biology (R.M.P., A.P.L.), Duke University School of Medicine, Durham, NC.
  • Atkins S; Department of Pediatrics, Division of Cardiology (B.S., R.J.K., S.A., A.P.L.), Duke University School of Medicine, Durham, NC.
  • Fatahian AN; 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.
  • Davis K; Nora Eccles Harrison Cardiovascular Research and Training Institute (K.D., M.W.S., J.S.W., S.F.), University of Utah, Salt Lake City.
  • Szulik MW; Nora Eccles Harrison Cardiovascular Research and Training Institute (K.D., M.W.S., J.S.W., S.F.), University of Utah, Salt Lake City.
  • Goodman MA; 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.
  • Hathaway MA; 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.
  • Chi E; 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.
  • Word TA; Department of Molecular Physiology and Biophysics (T.A.W., X.H.T.W.), Baylor College of Medicine, Houston, TX.
  • Tunuguntla H; Department of Medicine and Pediatrics, Section of Cardiology (H.T., S.W.D., X.H.T.W.), Baylor College of Medicine, Houston, TX.
  • Denfield SW; Department of Medicine and Pediatrics, Section of Cardiology (H.T., S.W.D., X.H.T.W.), Baylor College of Medicine, Houston, TX.
  • Wehrens XHT; Department of Molecular Physiology and Biophysics (T.A.W., X.H.T.W.), Baylor College of Medicine, Houston, TX.
  • Whitehead KJ; Department of Medicine and Pediatrics, Section of Cardiology (H.T., S.W.D., X.H.T.W.), Baylor College of Medicine, Houston, TX.
  • Abdelnasser HY; Department of Neuroscience, Cardiovascular Research Institute, and Center for Space Medicine (X.H.T.W.), Baylor College of Medicine, Houston, TX.
  • Warren JS; Division of Cardiovascular Medicine, Department of Internal Medicine (K.J.W.), University of Utah School of Medicine, Salt Lake City.
  • Wu M; Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, TX (H.Y.A., M.W.).
  • Franklin S; Nora Eccles Harrison Cardiovascular Research and Training Institute (K.D., M.W.S., J.S.W., S.F.), University of Utah, Salt Lake City.
  • Boudina S; Division of Cardiovascular Medicine (J.S.W.), University of Utah School of Medicine, Salt Lake City.
  • Landstrom AP; Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, TX (H.Y.A., M.W.).
Circ Heart Fail ; 16(12): e010351, 2023 12.
Article en En | MEDLINE | ID: mdl-38113297
ABSTRACT

BACKGROUND:

PRDM16 plays a role in myocardial development through TGF-ß (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 Prdm16Q187X 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-ß-associated transcripts. Homozygous Prdm16Q187X/Q187X mice demonstrated an underdeveloped compact myocardium and were embryonically lethal. Heterozygous Prdm16Q187X/WT mice demonstrated significantly smaller ventricular dimensions, heightened fibrosis, and age-dependent loss of TGF-ß 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-ß signaling.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Factor de Crecimiento Transformador beta / Proteínas de Unión al ADN / Insuficiencia Cardíaca / Cardiomiopatías Límite: Animals / Child, preschool / Female / Humans / Male / Newborn Idioma: En Revista: Circ Heart Fail Asunto de la revista: ANGIOLOGIA / CARDIOLOGIA Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Factor de Crecimiento Transformador beta / Proteínas de Unión al ADN / Insuficiencia Cardíaca / Cardiomiopatías Límite: Animals / Child, preschool / Female / Humans / Male / Newborn Idioma: En Revista: Circ Heart Fail Asunto de la revista: ANGIOLOGIA / CARDIOLOGIA Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos