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

Abstract

ImportanceNonsyndromic 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.ObjectiveTo identify a new gene for nsBAV.Design, Setting, and ParticipantsThis 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 2023. 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 MeasuresTo 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.ResultsA 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 RelevanceThis 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.

Directed Differentiation of Human Induced Pluripotent Stem Cells to Heart Valve Cells

“…Tangeretin could inhibit EndoMT in hiVECs ( Figure S14L ). These observations were consistent with the results of NOTCH1 deletion studies in vivo, 39 therefore, this protocol can be promising for its use in building heart valve disease models.…”

“…The scRNA-seq analysis demonstrated that NOTCH1 signaling pathway was important in the differentiation of hiPSCs into heart valve cells, and previous studies have reported that the NOTCH1 signaling pathway is critical for the development of heart valves. [37][38][39] In view of the crucial role of NOTCH1 in heart valve development, we sought to investigate whether inhibition of NOTCH1 might affect the differentiation of hiPSCs into heart valve cells. Tangeretin (an inhibitor of NOTCH1) significantly inhibited the differentiation of hiCLPMs and heart valve cells from hiPSCs (Figure S14C through S14G).…”

International Collaboration Identifies Gene Linked to Congenital Heart Defect

“…Her project eventually grew into a multinational collaboration involving 2 dozen investigators that identified a novel genetic cause for bicuspid aortic valve. 1 "We decided we wanted to go deeper and try to understand the wide spectrum of clinical expression of bicuspid aortic valve, " she said. "We realized that genetics may be the real story behind this inherited heart condition.…”

“…Her project eventually grew into a multinational collaboration involving 2 dozen investigators that identified a novel genetic cause for bicuspid aortic valve. 1…”

Whole Exome Sequencing Uncovers the Genetic Complexity of Bicuspid Aortic Valve in Families with Early Onset Complications

“…The prevalence of LVNC is generally increased in BAV cohorts, and mutation of KCNJ2, another potassium channel subunit, causes a syndromic presentation of BAV with extracardiac features in addition to arrhythmias (57). BAV and TAD also co-segregate with LVNC in some families with mutations in NKX2-5, TBX20 or MIB1, another Notch pathway regulator that was convincingly linked to BAV in recent studies and is recurrently mutated in the EBAV cohort (52,58,59). Our findings provide further evidence for a genetic link between cardiomyopathies, BAV, conduction abnormalities, and TAD that may contribute to early onset complications of BAV disease.…”