Novel Association of the NOTCH Pathway Regulator MIB1 Gene With the Development of Bicuspid Aortic Valve.

Autor:	Tessler I; Cardiology Department, Hadassah Medical Center, Jerusalem, Israel.; Sheba Medical Center, Ramat Gan, Israel.; Faculty of Medicine, the Hebrew University, Jerusalem, Israel.; Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Albuisson J; Genetics Department, Assistance Publique-Hȏpitaux de Paris, Hôpital Européen Georges Pompidou, National Referral Center for Rare Vascular Diseases, VASCERN MSA European Reference Center, Paris, France.; Université Paris Cité, INSERM, U970 PARCC, Paris, France.; Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer -UNICANCER, Dijon, France.; Genomic and Immunotherapy Medical Institute, Dijon, France., Piñeiro-Sabarís R; Intercellular Signaling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.; Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain., Verstraeten A; Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium.; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands., Kamber Kaya HE; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts.; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts., Siguero-Álvarez M; Intercellular Signaling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.; Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain., Goudot G; Université Paris Cité, INSERM, U970 PARCC, Paris, France.; Vascular Medicine Department, Assistance Publique-Hȏpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.; French Research Consortium RHU STOP-AS, Rouen, France., MacGrogan D; Intercellular Signaling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.; Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain., Luyckx I; Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium.; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands., Shpitzen S; Cardiology Department, Hadassah Medical Center, Jerusalem, Israel.; Faculty of Medicine, the Hebrew University, Jerusalem, Israel.; Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Levin G; Cardiology Department, Hadassah Medical Center, Jerusalem, Israel.; Faculty of Medicine, the Hebrew University, Jerusalem, Israel.; Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Kelman G; Faculty of Medicine, the Hebrew University, Jerusalem, Israel.; The Jerusalem Center for Personalized Computational Medicine, Jerusalem, Israel., Reshef N; Faculty of Medicine, the Hebrew University, Jerusalem, Israel.; The Jerusalem Center for Personalized Computational Medicine, Jerusalem, Israel., Mananet H; Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer -UNICANCER, Dijon, France.; Genomic and Immunotherapy Medical Institute, Dijon, France., Holdcraft J; Department of Anesthesiology, Boston University School of Medicine, Boston, Massachusetts., Muehlschlegel JD; Department of Anesthesiology, Boston University School of Medicine, Boston, Massachusetts., Peloso GM; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts., Oppenheim O; School of Neurobiology, Biochemistry and Biophysics, George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv, Israel., Cheng C; Université Paris Cité, INSERM, U970 PARCC, Paris, France.; Vascular Medicine Department, Assistance Publique-Hȏpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.; French Research Consortium RHU STOP-AS, Rouen, France., Mazzella JM; Université Paris Cité, INSERM, U970 PARCC, Paris, France.; Vascular Medicine Department, Assistance Publique-Hȏpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France., Andelfinger G; Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montreal, Montreal, Quebec, Canada., Mital S; Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada., Eriksson P; Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Solna, Sweden., Billon C; Genetics Department, Assistance Publique-Hȏpitaux de Paris, Hôpital Européen Georges Pompidou, National Referral Center for Rare Vascular Diseases, VASCERN MSA European Reference Center, Paris, France.; Université Paris Cité, INSERM, U970 PARCC, Paris, France., Heydarpour M; Department of Medicine, Division of Endocrinology, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts., Dietz HC; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland., Jeunemaitre X; Université Paris Cité, INSERM, U970 PARCC, Paris, France.; Vascular Medicine Department, Assistance Publique-Hȏpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France., Leitersdorf E; Cardiology Department, Hadassah Medical Center, Jerusalem, Israel.; Faculty of Medicine, the Hebrew University, Jerusalem, Israel.; Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Sprinzak D; School of Neurobiology, Biochemistry and Biophysics, George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv, Israel., Blacklow SC; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts.; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts., Body SC; Department of Anesthesiology, Boston University School of Medicine, Boston, Massachusetts., Carmi S; Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Loeys B; Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium.; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands., de la Pompa JL; Intercellular Signaling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.; Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain., Gilon D; Cardiology Department, Hadassah Medical Center, Jerusalem, Israel., Messas E; Université Paris Cité, INSERM, U970 PARCC, Paris, France.; Vascular Medicine Department, Assistance Publique-Hȏpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.; French Research Consortium RHU STOP-AS, Rouen, France., Durst R; Cardiology Department, Hadassah Medical Center, Jerusalem, Israel.; Faculty of Medicine, the Hebrew University, Jerusalem, Israel.; Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Jazyk:	angličtina
Zdroj:	JAMA cardiology [JAMA Cardiol] 2023 Aug 01; Vol. 8 (8), pp. 721-731.
DOI:	10.1001/jamacardio.2023.1469
Abstrakt:	Importance: Nonsyndromic bicuspid aortic valve (nsBAV) is the most common congenital heart valve malformation. BAV has a heritable component, yet only a few causative genes have been identified; understanding BAV genetics is a key point in developing personalized medicine. Objective: To identify a new gene for nsBAV. Design, Setting, and Participants: This was a comprehensive, multicenter, genetic association study based on candidate gene prioritization in a familial cohort followed by rare and common association studies in replication cohorts. Further validation was done using in vivo mice models. Study data were analyzed from October 2019 to October 2022. Three cohorts of patients with BAV were included in the study: (1) the discovery cohort was a large cohort of inherited cases from 29 pedigrees of French and Israeli origin; (2) the replication cohort 1 for rare variants included unrelated sporadic cases from various European ancestries; and (3) replication cohort 2 was a second validation cohort for common variants in unrelated sporadic cases from Europe and the US. Main Outcomes and Measures: To identify a candidate gene for nsBAV through analysis of familial cases exome sequencing and gene prioritization tools. Replication cohort 1 was searched for rare and predicted deleterious variants and genetic association. Replication cohort 2 was used to investigate the association of common variants with BAV. Results: A total of 938 patients with BAV were included in this study: 69 (7.4%) in the discovery cohort, 417 (44.5%) in replication cohort 1, and 452 (48.2%) in replication cohort 2. A novel human nsBAV gene, MINDBOMB1 homologue MIB1, was identified. MINDBOMB1 homologue (MIB1) is an E3-ubiquitin ligase essential for NOTCH-signal activation during heart development. In approximately 2% of nsBAV index cases from the discovery and replication 1 cohorts, rare MIB1 variants were detected, predicted to be damaging, and were significantly enriched compared with population-based controls (2% cases vs 0.9% controls; P = .03). In replication cohort 2, MIB1 risk haplotypes significantly associated with nsBAV were identified (permutation test, 1000 repeats; P = .02). Two genetically modified mice models carrying Mib1 variants identified in our cohort showed BAV on a NOTCH1-sensitized genetic background. Conclusions and Relevance: This genetic association study identified the MIB1 gene as associated with nsBAV. This underscores the crucial role of the NOTCH pathway in the pathophysiology of BAV and its potential as a target for future diagnostic and therapeutic intervention.
Databáze:	MEDLINE
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