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

Authors

Bo Sun
Omid M T Rouzbehani
Ryan J Kramer
Rajeshwary Ghosh
Robin M Perelli
Sage Atkins
Amir Nima Fatahian
Kathryn Davis
Marta W Szulik
Michael A Goodman
Marissa A Hathaway
Ellenor Chi
Tarah A Word
Hari Tunuguntla
Susan W Denfield
Xander H T Wehrens
Kevin J Whitehead
Hala Y Abdelnasser
Junco S Warren
Mingfu Wu
Sarah Franklin
Sihem Boudina
Andrew P Landstrom

Publication Date

12-1-2023

Journal

Circulation: Heart Failure

DOI

10.1161/CIRCHEARTFAILURE.122.010351

PMID

38113297

PMCID

PMC10752244

PubMedCentral® Posted Date

12-19-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Cardiomyopathies, Cell Proliferation, Signal Transduction, Transforming Growth Factor beta, Infant, Newborn, Myocytes, Cardiac, Child, Preschool, Cardiomyopathy, Dilated, Female, Cells, Cultured, Humans, Isolated Noncompaction of the Ventricular Myocardium, Mice, Animals, Myocardium, Apoptosis, Male, Heart Failure, Gene Knock-In Techniques, DNA-Binding Proteins, cardiomyopathy, cardiac maturation, transcription, genetic variants, induced pluripotent stem cells, TGFβ signaling

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 (iPSC-CMs) were generated from a proband hosting a Q187X nonsense variant as an in vitro model and underwent proliferative and transcriptional analyses. CRISPR-mediated knock-in mouse model hosting the Prdm16Q187X allele was generated and subjected to echocardiograph, histologic, and transcriptional analysis.

RESULTS: We report two probands with loss-of-function PRDM16 variants and pediatric left ventricular noncompaction cardiomyopathy (LVNC). One proband hosts a PRDM16-Q187X variant with LVNC and demonstrated infant-onset heart failure which was selected for further study. Induced pluripotent stem cells derived cardiomyocytes (IPSC-CMs) 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 TGFβ-associated transcripts. Homozygous Prdm16Q187X/Q187X mice demonstrated an underdeveloped compact myocardium and were embryonic lethal. Heterozygous Prdm16Q187X/WT mice demonstrated significantly smaller ventricular dimensions, heightened fibrosis, and age-dependent loss of TGFβ-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 TGFβ signaling.