<i>DVL1</i> variants and C-terminal deletions have differential effects on craniofacial development and WNT signaling
Bibliographic record
Abstract
Abstract Robinow Syndrome (RS) is a rare disease characterized by craniofacial malformations and limb shortening linked with mutations in seven WNT pathway genes. Our objective was to investigate the functional effects of frameshift mutations the intracellular adaptor protein, Dishevelled ( DVL1 ; c.1519 Δ T , p.Trp507Glyfs*142) on chicken craniofacial development. Misexpression of wt (wt) or mutant h DVL1 variants in vivo caused upper beak shortening (wt DVL1 n=8/14; DVL1 1519 Δ T 12/13). At early stages of development, the DVL1 1519 Δ T inhibited frontonasal mass narrowing, chondrogenesis, and proliferation. To test whether the phenotypes were caused due to the abnormal C-terminal peptide in DVL1 1519 Δ T , we designed two additional constructs. The DVL1 1519* (DVL1 507* ) retains first 30 amino acids of the C-terminus while DVL1 1431* (DVL1 477* ) removes the entire C-terminus. DVL1 1519* injected embryos had normal beaks while DVL1 1431* caused high mortality and the phenotypes were like the DVL1 1519 Δ T . In frontonasal micromass cultures, both DVL1 1519 Δ T and DVL1 1431* inhibited skeletogenesis while the DVL1 1519* resembled wt DVL1 and GFP cultures. In luciferase assays DVL1 1519 Δ T , DVL1 1519* and DVL1 1431* weakly activated the WNT canonical and non-canonical JNK-PCP pathways compared to wt DVL1 . Furthermore, we observed that variant DVL1 507*fs is stalled in the nucleus similar to hDVL1 477* , possibly due to the abnormal C-terminus interfering with the nuclear export sequence. wtDVL1 and DVL1 507* were distributed in nucleus and the cytoplasm. Our RS- DVL1 1519ΔT avian model recapitulates the broad face and jaw hypoplasia and demonstrates defects in both branches of WNT signaling. This is the first study to clarify the role of abnormal C-terminus in ADRS and to recognize the importance of an uncharacterized C-terminal sequence. Summary Statement Functional and biochemical studies on chicken embryos with the Robinow syndrome (RS) DVL1 variant demonstrate defects in skeletogenesis and both branches of WNT signaling. This is the first study to establish a link between the RS facial defects and the mutated C-terminal sequence. We identified first 30 amino acids of the DVL1 C-terminus are sufficient for normal development.
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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 | 0.000 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".