دورية أكاديمية
Wnt Signaling Interactor WTIP (Wilms Tumor Interacting Protein) Underlies Novel Mechanism for Cardiac Hypertrophy.
| العنوان: | Wnt Signaling Interactor WTIP (Wilms Tumor Interacting Protein) Underlies Novel Mechanism for Cardiac Hypertrophy. |
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| المؤلفون: | De Jong HN; Department of Genetics (H.N.D., R.C., M.S., E.A.A.), Stanford University, CA., Dewey FE; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Cordero P; Biomedical Informatics (P.C.), Stanford University, CA., Victorio RA; Brigham and Women's Hospital, Harvard University, Boston, MA (R.A.V., A.A.W., C.M.)., Kirillova A; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Huang Y; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Madhvani R; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Seo K; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Werdich AA; Brigham and Women's Hospital, Harvard University, Boston, MA (R.A.V., A.A.W., C.M.)., Lan F; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Orcholski M; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Liu WR; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Erbilgin A; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Wheeler MT; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Chen R; Department of Genetics (H.N.D., R.C., M.S., E.A.A.), Stanford University, CA., Pan S; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Kim YM; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Bommakanti K; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Marcou CA; Mayo Clinic, Rochester, MN (C.A.M., J.M.B., M.A.)., Bos JM; Mayo Clinic, Rochester, MN (C.A.M., J.M.B., M.A.)., Haddad F; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Ackerman M; Mayo Clinic, Rochester, MN (C.A.M., J.M.B., M.A.)., Vasan RS; Boston University School of Medicine, MA (R.S.V.)., MacRae C; Brigham and Women's Hospital, Harvard University, Boston, MA (R.A.V., A.A.W., C.M.)., Wu JC; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., de Jesus Perez V; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Snyder M; Department of Genetics (H.N.D., R.C., M.S., E.A.A.), Stanford University, CA., Parikh VN; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA., Ashley EA; Department of Genetics (H.N.D., R.C., M.S., E.A.A.), Stanford University, CA.; Department of Medicine (F.E.D., A.K., Y.H., R.M., K.S., F.L., M.O., W.R.L., A.E., M.T.W., S.P., Y.M.K., K.B., F.H., J.C.W., V.d.J.P., V.N.P., E.A.A.), Stanford University, CA. |
| المصدر: | Circulation. Genomic and precision medicine [Circ Genom Precis Med] 2022 Aug; Vol. 15 (4), pp. e003563. Date of Electronic Publication: 2022 Jun 07. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 101714113 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2574-8300 (Electronic) Linking ISSN: 25748300 NLM ISO Abbreviation: Circ Genom Precis Med Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Baltimore, MD] : Lippincott Williams & Wilkins, [2018]- |
| مواضيع طبية MeSH: | Co-Repressor Proteins/*metabolism , Cytoskeletal Proteins/*metabolism , Hypertrophy, Left Ventricular/*metabolism, Animals ; Calcium/metabolism ; Cardiomegaly/metabolism ; Cardiomyopathy, Hypertrophic/metabolism ; Humans ; Rats ; Verapamil |
| مستخلص: | 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. |
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| معلومات مُعتمدة: | R01 HL093328 United States HL NHLBI NIH HHS; K08 HL143185 United States HL NHLBI NIH HHS; R01 HL144843 United States HL NHLBI NIH HHS; R01 HL134776 United States HL NHLBI NIH HHS; U01 HG010218 United States HG NHGRI NIH HHS; R01 HL139664 United States HL NHLBI NIH HHS |
| فهرسة مساهمة: | Keywords: calcium; cardiomyopathy, hypertrophic; humans; induced pluripotent stem cells; myocytes, cardiac; zebra fish |
| المشرفين على المادة: | 0 (Co-Repressor Proteins) 0 (Cytoskeletal Proteins) 0 (WTIP protein, human) CJ0O37KU29 (Verapamil) SY7Q814VUP (Calcium) |
| تواريخ الأحداث: | Date Created: 20220607 Date Completed: 20220818 Latest Revision: 20230825 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC10445530 |
| DOI: | 10.1161/CIRCGEN.121.003563 |
| PMID: | 35671065 |
| قاعدة البيانات: | MEDLINE |
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