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

Publication ,  Journal Article
Sun, B; Rouzbehani, OMT; Kramer, RJ; Ghosh, R; Perelli, RM; Atkins, S; Fatahian, AN; Davis, K; Szulik, MW; Goodman, MA; Hathaway, MA; Chi, E ...
Published in: Circ Heart Fail
December 2023

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 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-β-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-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.

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Published In

Circ Heart Fail

DOI

EISSN

1941-3297

Publication Date

December 2023

Volume

16

Issue

12

Start / End Page

e010351

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta
  • Signal Transduction
  • Myocytes, Cardiac
  • Myocardium
  • Mice
  • Male
  • Infant, Newborn
  • Humans
  • Heart Failure
  • Gene Knock-In Techniques
 

Citation

APA
Chicago
ICMJE
MLA
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Sun, B., Rouzbehani, O. M. T., Kramer, R. J., Ghosh, R., Perelli, R. M., Atkins, S., … Landstrom, A. P. (2023). Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice. Circ Heart Fail, 16(12), e010351. https://doi.org/10.1161/CIRCHEARTFAILURE.122.010351
Sun, Bo, Omid M. T. Rouzbehani, Ryan J. Kramer, Rajeshwary Ghosh, Robin M. Perelli, Sage Atkins, Amir Nima Fatahian, et al. “Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.Circ Heart Fail 16, no. 12 (December 2023): e010351. https://doi.org/10.1161/CIRCHEARTFAILURE.122.010351.
Sun B, Rouzbehani OMT, Kramer RJ, Ghosh R, Perelli RM, Atkins S, et al. Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice. Circ Heart Fail. 2023 Dec;16(12):e010351.
Sun, Bo, et al. “Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.Circ Heart Fail, vol. 16, no. 12, Dec. 2023, p. e010351. Pubmed, doi:10.1161/CIRCHEARTFAILURE.122.010351.
Sun B, Rouzbehani OMT, Kramer RJ, Ghosh R, Perelli RM, Atkins S, Fatahian AN, Davis K, Szulik MW, Goodman MA, Hathaway MA, Chi E, Word TA, Tunuguntla H, Denfield SW, Wehrens XHT, Whitehead KJ, Abdelnasser HY, Warren JS, Wu M, Franklin S, Boudina S, Landstrom AP. Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice. Circ Heart Fail. 2023 Dec;16(12):e010351.

Published In

Circ Heart Fail

DOI

EISSN

1941-3297

Publication Date

December 2023

Volume

16

Issue

12

Start / End Page

e010351

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta
  • Signal Transduction
  • Myocytes, Cardiac
  • Myocardium
  • Mice
  • Male
  • Infant, Newborn
  • Humans
  • Heart Failure
  • Gene Knock-In Techniques