Independent Mutations at Arg181 and Arg274 of Vangl Proteins That Are Associated with Neural Tube Defects in Humans Decrease Protein Stability and Impair Membrane Targeting
Bibliographic record
Abstract
In vertebrates, Vangl proteins play important roles during embryogenesis, including establishing planar polarity and coordinating convergent extension movements. In mice, homozygosity for mutations in the Vangl1 and Vangl2 genes or combined heterozygosity for Vangl1/Vangl2 mutations causes the very severe neural tube defect (NTD) craniorachischisis. Recently, a number of patient-specific VANGL1 and VANGL2 protein mutations have been identified in familial and sporadic cases of mild and severe forms of NTDs. The biochemical nature of pathological effects in these mutations remains unknown. Of interest are two arginine residues, R181 and R274, that are highly conserved in Vangl protein homologues and found to be independently mutated in VANGL1 (R181Q and R274Q) and VANGL2 (R177H and R270H) in human cases of NTDs. The cellular and biochemical properties of R181Q and R274Q were established in transfected MDCK kidney epithelial cells and compared to those of wild-type (WT) Vangl1. Compared to that of WT, these mutations displayed impaired targeting to the plasma membrane and were instead detected in an intracellular endomembrane compartment that was positive for the endoplasmic reticulum. R181Q and R274Q showed impaired stability with significant reductions in measured half-lives from >20 h for WT protein to 9 and 5 h, respectively. These mutations have a cellular and biochemical phenotype that is indistinguishable from that of Vangl mutations known to cause craniorachichisis in mice (Lp). These results strongly suggest that R181 and R274 play critical roles in Vangl protein function and that their mutations cause neural tube defects in humans.
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How this classification was reachedexpand
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".