Deletion of <i>Sf3b4</i> in Neural Crest Cells Encapsulates the Variable Expressivity of Craniofacial Abnormalities Observed in Nager and Rodriguez Syndrome Patients
Bibliographic record
Abstract
Recently, both Nager syndrome and Rodriguez syndrome patients were identified to carry rare mutations in SF3B4 . Both disorders affect the face as well as the limb including both hands and feet. Nager syndrome patients survive and exhibit smaller jaw bones, smaller cheek bones, cleft palate, hearing problems as well as downward slanted eyelids. However, Rodriguez syndrome is much more severe, and patients often die before or soon after birth. We hypothesized that craniofacial abnormalities associated with reduced SF3B4 levels is due to tissue‐specific expression and requirement of this gene in neural crest cells. To generate a conditional mutant mouse line for Sf3b4, we used CRISPR/Cas9 to insert LoxP sequences in intron 1 and 3 of this gene. To test our hypothesis, we mated Sf3b4 conditional mutant mice to Wnt1 ‐ Cre2 transgenic mice to delete exons 2 and 3 specifically in neural crest cells. Heterozygous mutant embryos from these matings were normal. Sf3b4 L/L ; Wnt1‐Cre2 embryos have brain and craniofacial abnormalities, including abnormal forebrain, midbrain and hindbrain, hypoplasia of the maxillomandibular region and midline cleft. Majority of these embryos die before birth and the few mutants that are born are indistinguishable from their wildtype littermates. Additionally, we generated Sf3b4 L/‐; Wnt1‐Cre2 mutants with homozygous deletion of Sf3b4 in neural crest cells and heterozygous deletion of Sf3b4 in the body. These mutant embryos also had unfused frontonasal prominence and unfused and severely hypoplastic mandibular region. Sf3b4 L/‐; Wnt1‐Cre2 begin to die at E13.5 and none survive to birth. Thus, neural crest specific deletion of Sf3b4 in mice is able to model the craniofacial abnormalities presented in patients as well as capture the variable expressivity observed. Our model can further be used to uncover the splicing and molecular events regulated by SF3B4 during craniofacial 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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".