Notch Pathway Regulatory Protein MIB1: A Novel Gene For Nonsyndromic Bicuspid Aortic Valve
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Bibliographic record
Abstract
Objective: Bicuspid aortic valve (BAV) is the most common congenital heart malformation (>1%). Patients with BAV are at risk to develop complications, some are life threatening. Previous studies have linked mutations in NOTCH1, SMAD6 and GATA4 to the trait. However, the majority of BAV genetics remains obscure. In this study, we aimed to identify genes associated with BAV. Methods: Genetic analysis combining familial exome sequencing in 69 cases of non-syndromic BAV from 28 pedigrees of Israeli and French origin, targeted resequencing of candidate genes, and exome data reanalysis in more than 400 sporadic cases. Results: We identified MINDBOMB1 (MIB1) as a promising candidate gene. MIB1 has a key role in the ubiquitination of NOTCH ligands cytoplasmic tails. We identified three nonsense and three missense variants. The missense variant V934F, which was identified in a family of two cases, was previously identified in a familial case of Left Ventricular Noncompaction, and it leads to decrease JAG1 (the main NOTCH1 ligand) ubiquitination. Mouse model of MIB1 V934F and loss-of-function variants die from aortic valve dysfunction. A MIB1 inactivation mouse model caused BAV. The other variants were found in sporadic cases: The three nonsense variants R769*, R1001*, R97* lead to a loss of function of MIB1. The missense variants D380N was a de-novo mutation, and was previously shown to affects the interaction of MIB1 with its ligands. The last variant is of unknown function, but is predicted to be damaging (CADD score 14). We are conducting additional mouse models, as well as cellular and molecular characterization of the three missense variants, to refine the impact of it in NOTCH1 pathway deregulation. Conclusions: Our genetic study, based on a familial cohort, has led to identification of MIB1 as novel gene for BAV, underscoring the role of NOTCH pathway in the pathophysiology of the disease.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it