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Association of MIB1 Gene With Development of Bicuspid Aortic Valve
Quick Takes
- This genetic association study identified the gene MINDBOMB1 homologue MIB1, involved in NOTCH-signal activation during heart development, as associated with nonsyndromic bicuspid aortic valve (nsBAV).
- These findings help underscore the crucial role of the NOTCH pathway in the pathophysiology of BAV.
Study Questions:
Can a candidate gene be identified for nonsyndromic bicuspid aortic valve (nsBAV)?
Methods:
A comprehensive, multicenter, genetic association study based on candidate gene prioritization in a familial cohort (the discovery cohort) was followed by rare and common association studies in two replication cohorts, with further validation using in vivo mouse models. The discovery cohort was a large cohort of inherited cases of nsBAV (included if ≥1 relative had BAV or thoracic aortic aneurysm and excluding patients felt to have a syndromic condition) from 29 pedigrees of French and Israeli origin; replication cohort 1 for rare variants included unrelated sporadic cases from various European ancestries, and replication cohort 2 was a second validation cohort for common variants in unrelated sporadic cases from Europe and the United States. A MINDBOMB1 (MIB1) variant mouse line was created using clustered regularly spaced short palindromic repeats (CRISPR) RNA with microinjections at 1-cell stage fertilized mouse embryos.
Results:
A total of 938 patients with BAV were included in the study, including 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 = 0.03). In replication cohort 2, MIB1 risk haplotypes significantly associated with nsBAV were identified (permutation test, 1,000 repeats; p = 0.02). Two genetically modified mouse models carrying Mib1 variants identified in the cohort showed BAV on a NOTCH1-sensitized genetic background.
Conclusions:
This genetic association study identified the MIB1 gene to be associated with nsBAV. The authors conclude that 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.
Perspective:
BAV genetics are complex, but only a few genes (NOTCH1, GATA6, and SMAD6) have been associated with nsBAV in humans. The NOTCH pathway is a cell-cell communication pathway involved in multiple developmental processes; NOTCH signaling regulates aortic valve morphogenesis, and its disruption causes aortic valve disease both in humans and mice. This study used human genetic associations to identify MIB1 as a novel gene associated with nsBAV in humans, and constructed functional models in mice to confirm the association. These findings suggest the involvement of MIB1 in the development of nsBAV and highlight the role of the NOTCH pathway as a potential contributor to nsBAV inheritance and pathophysiology. Further investigation of other genes in the NOTCH pathway may be warranted to help further characterize the development of nsBAV.
Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Congenital Heart Disease and Pediatric Cardiology, Valvular Heart Disease, Vascular Medicine, Genetic Arrhythmic Conditions, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and CHD and Pediatrics, Cardiac Surgery and VHD, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias
Keywords: Aortic Aneurysm, Thoracic, Bicuspid Aortic Valve Disease, Genetics, Haplotypes, Heart Defects, Congenital, Heart Valve Diseases, Morphogenesis, Pedigree, RNA, Ubiquitin-Protein Ligases
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