A homozygous nonsense mutation (c.214C→A) in the biliverdin reductase alpha gene ( <i>BLVRA)</i> results in accumulation of biliverdin during episodes of cholestasis
Bibliographic record
Abstract
BACKGROUND: Green jaundice is a rare finding usually associated with end-stage liver disease. OBJECTIVE The authors investigated two unrelated Inuit women from different geographical areas in Greenland who had episodes of green jaundice associated with biliary obstruction. METHODS AND RESULTS: The crises were accompanied by increased biochemical markers of cholestasis, together with absent or moderate hyperbilirubinaemia. In contrast, high-performance liquid chromatography tandem mass spectrometry showed hypercholanaemia and high concentrations of biliverdin IXα in serum, urine, bile and milk. Hyperbiliverdinaemia disappeared after surgical correction of the cholestasis. Analysis of the coding sequence of the biliverdin reductase alpha (BVRα) gene (BLVRA) detected three single-nucleotide polymorphisms: c.90G→A, c.214C→A and c.743A→C, which result in p.Ala3Thr, p.Ser44X and p.Gly220Gly, respectively. With the use of TaqMan probes, homozygosity for c.214C→A was found in both patients. Both parents of one of these patients were heterozygous for the inactivating mutation. Her brother was homozygous for normal alleles. Although her sister was also homozygous for the c.214C→A mutation, she had never had hyperbiliverdinaemia or cholestasis. With the use of human liver RNA, the BVRα coding sequence was cloned, and the variant containing c.214C→A was generated by site-directed mutagenesis. Both proteins were expressed in human hepatoma liver cells and Xenopus laevis oocytes. Immunoblotting, immunofluorescence and functional assays of BVRα activity revealed that the mutated sequence generates a truncated protein with no catalytic activity. CONCLUSION: This is the first report of a homozygous BLVRA inactivating mutation indicating that the complete absence of BVRα activity is a non-lethal condition, the most evident phenotypic characteristic of which is the appearance of green jaundice accompanying cholestasis episodes.
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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 | 0.001 |
| 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) | 0.000 | 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".