Mechanistic Link Between Primary Ciliary Dysfunction and Syndromic Congenital Heart Defects

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Summary of  PLOS Biology  https://doi.org/10.1371/journal.pbio.3003902 
Dr. Canan Doganli  et al.

Points

Congenital heart disease affects approximately two in every 100 newborns globally and frequently co-occurs with multi-organ structural malformations.
University of Copenhagen researchers identified a cellular signaling hub inside the primary cilium that regulates embryonic cardiac muscle differentiation.
Genetic analyses of patient cohorts revealed an increased burden of rare TAB2 and TAK1 variants in individuals with extra-cardiac developmental abnormalities.
Laboratory experiments confirmed that TAK1, TAB2, and PKA-Cα interact at the primary cilium to transduce non-canonical TGFB and BMP signaling cascades.
Disruption of ciliary TAK1 localization in zebrafish models downregulated key cardiac transcription factors, sarcomeric proteins, and extracellular matrix gene expression.

Summary

This study evaluated the genetic and molecular role of non-canonical transforming growth factor-beta (TGFB) and bone morphogenetic protein (BMP) signaling at the primary cilium during cardiac morphogenesis and syndromic congenital heart disease (CHD). Globally, CHD impacts approximately 2 in every 100 live births, frequently co-occurring with extra-cardiac malformations. Led by Lars Allan Larsen and Søren Tvorup Christensen at the University of Copenhagen, the investigation analyzed genetic data across several thousand patients to determine how pathogenic variants in genes encoding transforming growth factor-beta-activated kinase 1 (TAK1/MAP3K7), TAB2, and protein kinase A catalytic subunit alpha (PKA-Cα/PRKACA) disrupt embryonic cardiogenesis.

Genetic sequencing of CHD patient cohorts revealed a statistically significant burden of rare, pathogenic TAB2 and TAK1 variants, specifically enriched in individuals presenting with syndromic CHD and extra-cardiac structural anomalies. In vitro molecular assays utilizing human and mouse stem cell models demonstrated that TAK1, TAB2, and PKA-Cα form an active signaling complex localized specifically to the primary cilium during cardiomyogenesis. Stimulation with TGFB/BMP ligands enhanced TAK1 activation at the ciliary hub, whereas patient-derived TAK1 variants impaired its ciliary localization and inhibited downstream ciliary signaling, thereby disrupting progenitor differentiation into functional cardiomyocytes.

In vivo functional modeling using zebrafish tak1 and tab2 knockout mutants confirmed impaired cardiac development and severe multi-organ malformations. Transcriptomic analysis of tak1 mutant hearts revealed marked downregulation of genes encoding core cardiac transcription factors, sarcomeric contractile proteins, and extracellular matrix components. The authors conclude that primary ciliary TAK1 signaling serves as an essential regulatory hub for embryonic cardiogenesis, providing a mechanistic framework that links primary ciliopathies to syndromic CHD and multi-system developmental disorders.

Link to the article: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003902

References

Doganli, C., Thomsen, O. K., Baird, D. A., Ali, Y., Sarusie, M. V. K., Audain, E., Jessen, L. J., Truelsen, P. M., Mogensen, J. B., Holm, M. S., Apolínová, K., Buttò, L., Diamanti, M., Fialová, J. L., Wade, E. M., Robertson, S. P., Pedersen, L. B., Argiro, L., Lescroart, F., … Larsen, L. A. (2026). TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development. PLOS Biology, 24(8), e3003902. https://doi.org/10.1371/journal.pbio.3003902