Mitral Valve Prolapse Caused by TLL1 Gain-of-Function Mutation
Bibliographic record
Abstract
BACKGROUND: Mitral valve prolapse (MVP) is a common cardiac valvular anomaly that can be caused by mutations in genes of various biologic pathways. Individuals of 3 generations of a kindred presented with an apparently dominant heredity of isolated MVP. METHODS: Clinical evaluation and echocardiography were performed for all complying members of a family (n = 13). Whole exome and genome sequencing data of 2 affected individuals were analyzed, delineating shared heterozygous variants, and then further tested for segregation within the kindred (Sanger sequencing). Tolloid-like 1 (TLL1) enzymatic activity was assayed in media of HEK293 cells transfected with wild-type vs mutant TLL1. RESULTS: The only heterozygous variant segregating in the affected kindred as expected for dominant heredity of MVP was p.T253A, within the catalytic domain of TLL1. Of 8 heterozygotes, 6 had MVP and 2 had trivial mitral regurgitation. An activity assay in the extracellular media of the HEK293-transfected cells showed that, over time (12 hours), the enzymatic activity of the mutated TLL1 protein was 3.4-fold higher than that of the wild-type. CONCLUSIONS: Our genetic and biochemical studies show that a TLL1 gain-of-function mutation, prolonging the half-life of TLL1 active protein in the extracellular matrix, causes autosomal dominant MVP with variable expressivity. TLL1 encodes an extracellular metalloprotease regulating extracellular matrix composition and maintenance. In previous work, heterozygous loss-of-function TLL1 mutations have been shown to cause autosomal dominant atrial septal defects. Our findings enable novel insights into the molecular pathways of valvular physiology and disease, the role of TLL1 in human development, and the differing phenotypes in loss-of-function and gain-of-function mutations of the same gene.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".