Wnt Signaling Interactor WTIP (Wilms Tumor Interacting Protein) Underlies Novel Mechanism for Cardiac Hypertrophy
- De Jong, H.N., Dewey, F.E., Cordero, P., Victorio, R.A., Kirillova, A., Huang, Y., Madhvani, R., Seo, K., Werdich, A.A., Lan, F., Orcholski, M., Robert Liu, W., Erbilgin, A., Wheeler, M.T., Chen, R., Pan, S., Kim, Y.M., Bommakanti, K., Marcou, C.A., Martijn Bos, J., Haddad, F., Ackerman, M., Vasan, R.S., MacRae, C., Wu, J.C., de Jesus Perez, V., Snyder, M., Parikh, V.N., Ashley, E.A.
- Circulation. Genomic and precision medicine 15(4): e003563 (Journal)
- Registered Authors
- MacRae, Calum A.
- calcium, humans, infant, newborn, muscle cells, zebra fish
- MeSH Terms
- Cardiomyopathy, Hypertrophic/metabolism
- Co-Repressor Proteins/metabolism*
- Cytoskeletal Proteins/metabolism*
- Hypertrophy, Left Ventricular/metabolism*
- 35671065 Full text @ Circ Genom Precis Med
De Jong, H.N., Dewey, F.E., Cordero, P., Victorio, R.A., Kirillova, A., Huang, Y., Madhvani, R., Seo, K., Werdich, A.A., Lan, F., Orcholski, M., Robert Liu, W., Erbilgin, A., Wheeler, M.T., Chen, R., Pan, S., Kim, Y.M., Bommakanti, K., Marcou, C.A., Martijn Bos, J., Haddad, F., Ackerman, M., Vasan, R.S., MacRae, C., Wu, J.C., de Jesus Perez, V., Snyder, M., Parikh, V.N., Ashley, E.A. (2022) Wnt Signaling Interactor WTIP (Wilms Tumor Interacting Protein) Underlies Novel Mechanism for Cardiac Hypertrophy. Circulation. Genomic and precision medicine. 15(4):e003563.
Background The study of hypertrophic cardiomyopathy (HCM)-a severe Mendelian disease-can yield insight into the mechanisms underlying the complex trait of cardiac hypertrophy. To date, most genetic variants associated with HCM have been found in sarcomeric genes. Here, we describe a novel HCM-associated variant in the noncanonical Wnt signaling interactor WTIP (Wilms tumor interacting protein) and provide evidence of a role for WTIP in complex disease.
Methods In a family affected by HCM, we used exome sequencing and identity-by-descent analysis to identify a novel variant in WTIP (p.Y233F). We knocked down WTIP in isolated neonatal rat ventricular myocytes with lentivirally delivered shRNAs and in Danio rerio via morpholino injection. We performed weighted gene coexpression network analysis for WTIP in human cardiac tissue, as well as association analysis for WTIP variation and left ventricular hypertrophy. Finally, we generated induced pluripotent stem cell-derived cardiomyocytes from patient tissue, characterized size and calcium cycling, and determined the effect of verapamil treatment on calcium dynamics.
Results WTIP knockdown caused hypertrophy in neonatal rat ventricular myocytes and increased cardiac hypertrophy, peak calcium, and resting calcium in D rerio. Network analysis of human cardiac tissue indicated WTIP as a central coordinator of prohypertrophic networks, while common variation at the WTIP locus was associated with human left ventricular hypertrophy. Patient-derived WTIP p.Y233F-induced pluripotent stem cell-derived cardiomyocytes recapitulated cellular hypertrophy and increased resting calcium, which was ameliorated by verapamil.
Conclusions We demonstrate that a novel genetic variant found in a family with HCM disrupts binding to a known Wnt signaling protein, misregulating cardiomyocyte calcium dynamics. Further, in orthogonal model systems, we show that expression of the gene WTIP is important in complex cardiac hypertrophy phenotypes. These findings, derived from the observation of a rare Mendelian disease variant, uncover a novel disease mechanism with implications across diverse forms of cardiac hypertrophy.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes