A Mouse Model for Cerebro‐Costo‐Mandibular Syndrome (CCMS) with an Intronic Deletion in <i>SnrpB</i>
Bibliographic record
Abstract
SNRPB , an essential effector of the spliceosomal complex, is implicated in the splicing of mature mRNA and is mutated in a rare craniofacial disorder known as Cerebro‐costo‐mandibular syndrome (CCMS). Most CCMS patients carry point mutations in the highly conserved alternative exon 2 (AE2) of SNRPB , leading to increased inclusion of a pre‐termination codon (PTC) and reduced levels of the protein‐coding transcript. Given that SNRPB is implicated in all steps of splicing, it was thought that its requirement would be equivalent in all cells and tissues. However, CCMS patients predominantly present with micrognathia and rib defects with variable penetrance. We hypothesize that a subset of transcripts is highly sensitive to the levels of SNRPB during development and is tissue specific. Here, we are generating a mouse model for CCMS to uncover those transcripts that play an essential role in craniofacial development. Using the CRISPR/Cas9 gene‐editing system, we developed a mutant mouse line with a 61 base‐pair (bp) intronic deletion upstream of the AE2. Interestingly, a subset of the heterozygous and homozygous embryos and pups for this deletion show morphological abnormalities in the face, head, ribs, and limbs. Moreover, a significant percentage of the mutants with the 61‐bp deletion die in their first year of life. A subgroup of the heterozygous and homozygous mutant embryos show increased inclusion of the PTC containing AE2 and reduced SNRPB protein levels. We presume that this predominant inclusion of the AE2 induces non‐sense mediated decay resulting in decreased levels of SNRPB. As our data suggest that the 61 bp intronic sequence plays a critical role in regulating SNRPB levels in mice, we are currently investigating if similar intronic sequences in intron 2 of human SNRPB are involved in the preferential splicing of AE2. In addition, we generated a SnrpB conditional knockout mouse model, which will be used in parallel with the deletion model to investigate the cell‐type‐specific roles of SNRPB during craniofacial development. Our novel model for CCMS will further our understanding of the role of SNRPB in craniofacial development. Support or Funding Information Canadian Institutes of Health Research (CIHR)
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
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".