<i>CblX</i> is a New Cobalamin Syndrome Affecting Craniofacial Development
Bibliographic record
Abstract
Combined methylmalonic acidemia and homocystinuria ( cblC type), an inherited disorder of cobalamin (vitamin B 12 ) metabolism, is a rare metabolic and multi‐systemic disease caused by mutations in MMACHC . Patients with cblC can have severe neurodevelopmental defects including microcephaly, hydrocephaly, and seizures as well as renal, cardiac and hematological defects. Recently, two new variants of cblC were discovered and termed cblX and cblX ‐like. Rather than being due to mutations in MMACHC , cblX and cblX ‐like result from homozygous mutations in the transcription cofactor HCFC1 and its transcription factor partner RONIN (THAP11) , respectively. Patients with either HCFC1 or RONIN mutations were shown to have a dramatic reduction in MMACHC transcription. We have known that HCFC1 is an obligatory partner for RONIN and we have previously shown that the HCFC1/RONIN transcriptional complex directly regulates mouse Mmachc expression. These findings suggest that cblX and cblX ‐like disorders comprise a novel family of rare and severe cblC ‐like disorders that are transcriptional in nature. To better understand the cellular and molecular mechanisms underlying the pathophysiology of these devastating neurodevelopmental diseases, we have generated Hcfc1 A115V and Ronin F80L mice, which have the same point mutations observed in cblX and cblX ‐like patients. Both Hcfc1 Y/A115V hemizygous and Ronin F80L/F80L homozygous mice exhibit defects in cobalamin metabolism consistent with an inherited vitamin B 12 disorder, as well as defects that recapitulate those observed in the human cblX and cblX ‐like patients, including severe brain developmental defects, cardiac malformations, and anemia. Additionally, these mice also exhibit craniofacial deformities, a developmental phenotype that has not been previously linked to vitamin B 12 . Our data identifies, for the first time, a role for RONIN/HCFC1 in craniofacial development. Together, the phenotypic and molecular data confirm that the Ronin F80L and Hcfc1 A115V mouse models will serve as powerful tools to further uncover the pathophysiology of this complex family of diseases, as well as to achieve a better understanding of the complexities of craniofacial development. Support or Funding Information This work is supported by R01 DE028298.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 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".