Abnormal WNT5A Signaling Causes Mandibular Hypoplasia in Robinow Syndrome
Bibliographic record
Abstract
The study of rare genetic diseases provides valuable insights into human gene function. Here, we investigate dominant Robinow syndrome (RS), which affects the WNT5A signaling pathway. Autosomal dominant RS is caused by missense mutations in WNT5A or nonsense mutations in the adaptor protein DVL1 or DVL3. The recessive form of the disease is caused by loss-of-function mutations in the receptor ROR2. RS is characterized by hypertelorism, midface, and mandibular hypoplasia. Here, we focus on the missense mutations in WNT5A, since the impact on function is difficult to predict from in silico analysis. We used chicken embryo to express wild-type or 2 mutant versions of human WNT5A in the mandible and then examined the morphologic, cellular, and molecular effects. The 3 experimental viruses—wt WNT5A, WNT5A C83S , or WNT5A C182R —all caused shortening of the mandible on the injected side as compared with GFP controls. Although the phenotypes initially appeared similar, we uncovered specific disruption of chondrocyte polarity and shape, inhibition of cell migration, differences in target gene expression, and absence of JNK signaling only in the presence of mutant viruses. In addition, the missense mutations do not appear to block receptor binding, since in paracrine experiments, the mutant protein inhibits cell migration. In this study, we ruled out a straightforward gain or loss of function caused by the WNT5A missense mutations. Instead, the mutations are likely redirecting WNT signaling away from JNK-PCP toward other noncanonical pathways. We conclude that in RS, WNT5A missense mutations have dominant neomorphic effects that interfere with the function of the wild-type protein.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.002 | 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 | 0.001 | 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".