Svitlana Podliesna1, Julian Delanne2, Lindsey Miller3, David J Tester4, Merujan Uzunyan3, Shoji Yano3, Mischa Klerk1, Bryan C Cannon4, Apichai Khongphatthanayothin5, Gabriel Laurent6, Geraldine Bertaux7, Sylvie Falcon-Eicher7, Shengnan Wu8, Hai-Yun Yen8, Hanlin Gao8, Arthur A M Wilde9, Laurence Faivre10, Michael J Ackerman4, Elisabeth M Lodder1, Connie R Bezzina11. 1. Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, Amsterdam, The Netherlands. 2. Centre de Génétique, Hôpital d'Enfants, Dijon, France. 3. USC Keck School of Medicine, LAC+USC Medical Center, Los Angeles, California. 4. Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, Minnesota. 5. USC Keck School of Medicine, LAC+USC Medical Center, Los Angeles, California; Bangkok General Hospital and Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. 6. Centre de compétence pour les troubles du rythme cardiaque d'origine génétique, CHU Dijon-Bourgogne, Dijon, France; Service de rythmologie Centre Hospitalier Universitaire Le Bocage 2, Dijon, France. 7. Centre de compétence pour les troubles du rythme cardiaque d'origine génétique, CHU Dijon-Bourgogne, Dijon, France. 8. Fulgent Genetics, Temple City, California. 9. Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, Amsterdam, The Netherlands; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia. 10. Centre de Génétique, Hôpital d'Enfants, Dijon, France; Equipe GAD, UMR1231, FHU TRANSLAD et Institut GIMI, CHU Dijon-Bourgogne et Université de Bourgogne-Franche Comté, Dijon, France. 11. Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: c.r.bezzina@amc.uva.nl.
Abstract
BACKGROUND: Rare genetic variants in TNNI3K encoding troponin-I interacting kinase have been linked to a distinct syndrome consisting primarily of supraventricular tachycardias and variably expressed conduction disturbance and dilated cardiomyopathy in 2 families. OBJECTIVE: The purpose of this study was to identify new genetic variants associated with inherited supraventricular tachycardias, cardiac conduction disease, and cardiomyopathy. METHODS: We conducted next generation sequencing in 3 independent multigenerational families with atrial/junctional tachycardia with or without conduction disturbance, dilated cardiomyopathy, and sudden death. We also assessed the effect of identified variant on protein autophosphorylation. RESULTS: In this study, we uncovered the same ultra-rare genetic variant in TNNI3K (c.2302G>A, p.Glu768Lys), which co-segregated with disease features in all affected individuals (n = 23) from all 3 families. TNNI3K harboring the TNNI3K-p.Glu768Lys variant displayed enhanced kinase activity, in line with expectations from previous mouse studies that demonstrated increased conduction indices and procardiomyopathic effects with increased levels of Tnni3k. CONCLUSION: This study corroborates further the causal link between rare genetic variation in TNNI3K and this distinct complex phenotype, and points to enhanced kinase activity of TNNI3K as the underlying pathobiological mechanism.
BACKGROUND: Rare genetic variants in TNNI3K encoding troponin-I interacting kinase have been linked to a distinct syndrome consisting primarily of supraventricular tachycardias and variably expressed conduction disturbance and dilated cardiomyopathy in 2 families. OBJECTIVE: The purpose of this study was to identify new genetic variants associated with inherited supraventricular tachycardias, cardiac conduction disease, and cardiomyopathy. METHODS: We conducted next generation sequencing in 3 independent multigenerational families with atrial/junctional tachycardia with or without conduction disturbance, dilated cardiomyopathy, and sudden death. We also assessed the effect of identified variant on protein autophosphorylation. RESULTS: In this study, we uncovered the same ultra-rare genetic variant in TNNI3K (c.2302G>A, p.Glu768Lys), which co-segregated with disease features in all affected individuals (n = 23) from all 3 families. TNNI3K harboring the TNNI3K-p.Glu768Lys variant displayed enhanced kinase activity, in line with expectations from previous mouse studies that demonstrated increased conduction indices and procardiomyopathic effects with increased levels of Tnni3k. CONCLUSION: This study corroborates further the causal link between rare genetic variation in TNNI3K and this distinct complex phenotype, and points to enhanced kinase activity of TNNI3K as the underlying pathobiological mechanism.
Authors: Peiheng Gan; Catalin Baicu; Hirofumi Watanabe; Kristy Wang; Ge Tao; Daniel P Judge; Michael R Zile; Takako Makita; Rupak Mukherjee; Henry M Sucov Journal: Hum Mol Genet Date: 2021-01-06 Impact factor: 6.150
Authors: Steffany Grondin; Brianna Davies; Julia Cadrin-Tourigny; Christian Steinberg; Christopher C Cheung; Paloma Jorda; Jeffrey S Healey; Martin S Green; Shubhayan Sanatani; Wael Alqarawi; Paul Angaran; Laura Arbour; Pavel Antiperovitch; Habib Khan; Richard Leather; Peter G Guerra; Lena Rivard; Christopher S Simpson; Martin Gardner; Ciorsti MacIntyre; Colette Seifer; Anne Fournier; Jacqueline Joza; Michael H Gollob; Guillaume Lettre; Mario Talajic; Zachary W Laksman; Jason D Roberts; Andrew D Krahn; Rafik Tadros Journal: Eur Heart J Date: 2022-08-21 Impact factor: 35.855
Authors: Peiheng Gan; Michaela Patterson; Alexa Velasquez; Kristy Wang; Di Tian; Jolene J Windle; Ge Tao; Daniel P Judge; Takako Makita; Thomas J Park; Henry M Sucov Journal: PLoS Genet Date: 2019-10-07 Impact factor: 5.917