TY - JOUR
T1 - Wnt Signaling Interactor WTIP (Wilms Tumor Interacting Protein) Underlies Novel Mechanism for Cardiac Hypertrophy
AU - De Jong, Hannah N.
AU - Dewey, Frederick E.
AU - Cordero, Pablo
AU - Victorio, Rachelle A.
AU - Kirillova, Anna
AU - Huang, Yong
AU - Madhvani, Roshni
AU - Seo, Kinya
AU - Werdich, Andreas A.
AU - Lan, Feng
AU - Orcholski, Mark
AU - Liu, W. Robert
AU - Erbilgin, Ayca
AU - Wheeler, Matthew T.
AU - Chen, Rui
AU - Pan, Stephen
AU - Kim, Young M.
AU - Bommakanti, Krishna
AU - Marcou, Cherisse A.
AU - Bos, J. Martijn
AU - Haddad, Francois
AU - Ackerman, Michael
AU - Vasan, Ramachandran S.
AU - Macrae, Calum
AU - Wu, Joseph C.
AU - De Jesus Perez, Vinicio
AU - Snyder, Michael
AU - Parikh, Victoria N.
AU - Ashley, Euan A.
N1 - Publisher Copyright:
© 2022 Lippincott Williams and Wilkins. All rights reserved.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - Background: The study of hypertrophic cardiomyopathy (HCM) 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 short hairpin ribonucleic acids 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.
AB - Background: The study of hypertrophic cardiomyopathy (HCM) 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 short hairpin ribonucleic acids 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.
KW - calcium
KW - cardiomyopathy, hypertrophic
KW - humans
KW - induced pluripotent stem cells
KW - myocytes, cardiac
KW - zebra fish
UR - http://www.scopus.com/inward/record.url?scp=85136311055&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85136311055&partnerID=8YFLogxK
U2 - 10.1161/CIRCGEN.121.003563
DO - 10.1161/CIRCGEN.121.003563
M3 - Article
C2 - 35671065
AN - SCOPUS:85136311055
SN - 1942-325X
VL - 15
SP - E003563
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 4
ER -