The following is a summary of “Novel Association of the NOTCH Pathway Regulator MIB1 Gene With the Development of Bicuspid Aortic Valve,” published in the July 2023 issue of Cardiology by Tessler et al. 

For a study, researchers aimed to evaluate a new gene for the Nonsyndromic bicuspid aortic valve (nsBAV). The study spanned multiple centers, and they prioritized candidate genes in a familial cohort. Subsequent rare and common association studies were conducted in replication cohorts, with further validation using in vivo mice models. 

Researchers analyzed data from October 2019 to October 2022, incorporating three cohorts of patients with bicuspid aortic valve (BAV): a discovery cohort from 29 French-Israeli pedigrees, a rare variant replication cohort with unrelated sporadic cases from diverse European ancestries, and a common variant validation cohort with unrelated sporadic cases from Europe and the US.

The study included 938 patients diagnosed with Bicuspid Aortic Valve (BAV) divided across three cohorts—69 (7.4%) in the discovery cohort, 417 (44.5%) in replication cohort 1, and 452 (48.2%) in replication cohort 2—revealed a novel human nsBAV gene, MINDBOMB1 homologue MIB1. MIB1, an E3-ubiquitin ligase crucial for NOTCH-signal activation in heart development, was identified.

Approximately 2% of nsBAV index cases from the discovery and replication 1 cohort displayed rare damaging MIB1 variants, significantly more prevalent than in population-based controls (2% cases vs. 0.9% controls; P = .03). In replication cohort 2, MIB1 risk haplotypes associated significantly with nsBAV (permutation test, 1000 repeats; P = .02). Two genetically modified mouse models, carrying Mib1 variants identified in the cohort, exhibited BAV on a NOTCH1-sensitized genetic background.

The MIB1 gene was pinpointed in this genetic association study as linked to nsBAV. This underscores the pivotal involvement of the NOTCH pathway in BAV’s pathophysiology, highlighting its potential as a target for upcoming diagnostic and therapeutic interventions.

Source: jamanetwork.com/journals/jamacardiology/article-abstract/2806407