دورية أكاديمية
أعرض في EDS

Genetic Burden of TNNI3K in Diagnostic Testing of Patients With Dilated Cardiomyopathy and Supraventricular Arrhythmias.

التفاصيل البيبلوغرافية
العنوان: Genetic Burden of TNNI3K in Diagnostic Testing of Patients With Dilated Cardiomyopathy and Supraventricular Arrhythmias.
المؤلفون: Pham C; Department of Experimental Cardiology (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., C.R.B., E.M.L.), Heart Center, Amsterdam UMC location University of Amsterdam, the Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., A.A.M.W., C.R.B., E.M.L.)., Andrzejczyk K; Department of Experimental Cardiology (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., C.R.B., E.M.L.), Heart Center, Amsterdam UMC location University of Amsterdam, the Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., A.A.M.W., C.R.B., E.M.L.)., Jurgens SJ; Department of Experimental Cardiology (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., C.R.B., E.M.L.), Heart Center, Amsterdam UMC location University of Amsterdam, the Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., A.A.M.W., C.R.B., E.M.L.).; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.J.J., S.A.L., P.T.E.).; Cardiovascular Research Center, Massachusetts General Hospital, Boston (S.J.J., S.A.L., P.T.E.)., Lekanne Deprez R; Department of Human Genetics, Amsterdam UMC location University of Amsterdam, the Netherlands (R.L.D., A.M.C.V., J.N., D.S.-M., P.R.J., E.M.L.)., Palm KCA; Department of Experimental Cardiology (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., C.R.B., E.M.L.), Heart Center, Amsterdam UMC location University of Amsterdam, the Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., A.A.M.W., C.R.B., E.M.L.)., Vermeer AMC; Department of Human Genetics, Amsterdam UMC location University of Amsterdam, the Netherlands (R.L.D., A.M.C.V., J.N., D.S.-M., P.R.J., E.M.L.)., Nijman J; Department of Human Genetics, Amsterdam UMC location University of Amsterdam, the Netherlands (R.L.D., A.M.C.V., J.N., D.S.-M., P.R.J., E.M.L.)., Christiaans I; Department of Genetics, University Medical Center Groningen, University of Groningen, the Netherlands (I.C.)., Barge-Schaapveld DQCM; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands (D.Q.C.M.B.-S.)., van Dessel PFHM; Department of Cardiology, Thorax Center Twente, Medisch Spectrum Twente (MST), Enschede, the Netherlands (P.F.H.M.v.D.)., Beekman L; Department of Experimental Cardiology (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., C.R.B., E.M.L.), Heart Center, Amsterdam UMC location University of Amsterdam, the Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., A.A.M.W., C.R.B., E.M.L.)., Choi SH; Department of Biostatistics, Boston University, MA (S.H.C.)., Lubitz SA; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.J.J., S.A.L., P.T.E.).; Cardiovascular Research Center, Massachusetts General Hospital, Boston (S.J.J., S.A.L., P.T.E.)., Skoric-Milosavljevic D; Department of Human Genetics, Amsterdam UMC location University of Amsterdam, the Netherlands (R.L.D., A.M.C.V., J.N., D.S.-M., P.R.J., E.M.L.)., van den Bersselaar L; Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (L.v.d.B.)., Jansen PR; Department of Human Genetics, Amsterdam UMC location University of Amsterdam, the Netherlands (R.L.D., A.M.C.V., J.N., D.S.-M., P.R.J., E.M.L.).; Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Complex Trait Genetics, the Netherlands (P.R.J.)., Copier JS; Department of Experimental Cardiology (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., C.R.B., E.M.L.), Heart Center, Amsterdam UMC location University of Amsterdam, the Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., A.A.M.W., C.R.B., E.M.L.)., Ellinor PT; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.J.J., S.A.L., P.T.E.).; Cardiovascular Research Center, Massachusetts General Hospital, Boston (S.J.J., S.A.L., P.T.E.)., Wilde AAM; Department of Cardiology (A.A.M.W.), Heart Center, Amsterdam UMC location University of Amsterdam, the Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., A.A.M.W., C.R.B., E.M.L.)., Bezzina CR; Department of Experimental Cardiology (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., C.R.B., E.M.L.), Heart Center, Amsterdam UMC location University of Amsterdam, the Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., A.A.M.W., C.R.B., E.M.L.)., Lodder EM; Department of Experimental Cardiology (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., C.R.B., E.M.L.), Heart Center, Amsterdam UMC location University of Amsterdam, the Netherlands.; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (C.P., K.A., S.J.J., K.C.A.P., L.B., J.S.C., A.A.M.W., C.R.B., E.M.L.).; Department of Human Genetics, Amsterdam UMC location University of Amsterdam, the Netherlands (R.L.D., A.M.C.V., J.N., D.S.-M., P.R.J., E.M.L.).
المصدر: Circulation. Genomic and precision medicine [Circ Genom Precis Med] 2023 Aug; Vol. 16 (4), pp. 328-336. Date of Electronic Publication: 2023 May 18.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
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: Cardiomyopathy, Dilated*/diagnosis , Cardiomyopathy, Dilated*/genetics, Humans ; Retrospective Studies ; Arrhythmias, Cardiac/genetics ; Genetic Testing ; Cardiac Conduction System Disease/genetics ; Protein Serine-Threonine Kinases/genetics
مستخلص: Background: Genetic variants in TNNI3K (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between TNNI3K variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function.
Methods: We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including TNNI3K . We further performed burden testing of TNNI3K in the UK Biobank. For 2 novel TNNI3K variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays.
Results: We demonstrate enrichment of rare coding TNNI3K variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between TNNI3K missense (but not loss-of-function) variants and DCM and atrial fibrillation. Furthermore, we demonstrate genetic segregation for 2 rare variants, TNNI3K-p.Ile512Thr and TNNI3K-p.His592Tyr, with phenotypes consisting of DCM, cardiac conduction disease, and supraventricular tachycardia, together with increased autophosphorylation. In contrast, TNNI3K-p.Arg556_Asn590del, a likely benign variant, demonstrated depleted autophosphorylation.
Conclusions: Our findings demonstrate an increased burden of rare coding TNNI3K variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic TNNI3K variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.
Competing Interests: Disclosures Dr Ellinor receives sponsored research support from Bayer AG and IBM Research; he has also served on advisory boards or consulted for Bayer AG, MyoKardia and Novartis. Dr Lubitz has received sponsored research support from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Fitbit, Medtronic, Premier, and IBM, and has consulted for Bristol Myers Squibb, Pfizer, Blackstone Life Sciences, and Invitae. The other authors report no conflicts.
التعليقات: Comment in: Circ Genom Precis Med. 2023 Aug;16(4):337-339. (PMID: 37325914)
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معلومات مُعتمدة: R01 HL157635 United States HL NHLBI NIH HHS; R01 HL139731 United States HL NHLBI NIH HHS; R01 HL157635 United States HL NHLBI NIH HHS; R01 HL157635 United States HL NHLBI NIH HHS; R01 HL092577 United States HL NHLBI NIH HHS
فهرسة مساهمة: Keywords: cardiac arrhythmias; dilated cardiomyopathy; genetics; phosphorylation
المشرفين على المادة: EC 2.7.11.1 (TNNI3K protein, human)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
تواريخ الأحداث: Date Created: 20230518 Date Completed: 20230817 Latest Revision: 20230822
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC10426786
DOI: 10.1161/CIRCGEN.122.003975
PMID: 37199186
قاعدة البيانات: MEDLINE
الوصف
تدمد:2574-8300
DOI:10.1161/CIRCGEN.122.003975