<i>OCRL1</i> Mutations in Dent 2 Patients Suggest a Mechanism for Phenotypic Variability
Bibliographic record
Abstract
BACKGROUND/AIMS: Dent disease is an X-linked renal proximal tubulopathy associated with mutations in CLCN5 (Dent 1) or OCRL1 (Dent 2). OCRL1 mutations also cause the oculocerebrorenal syndrome of Lowe. METHODS: Dent patients with normal sequence for CLCN5 were sequenced for mutations in OCRL1. By analyzing these and all other OCRL1 mutations reported, a model relating OCRL1 mutations to the resulting disease (Dent 2 or Lowe's) was developed. RESULTS: Six boys with Dent disease had novel OCRL1 mutations: two missense (R301H, G304E) and four mutations predicted to produce premature termination codons (L56DfsX1, S149X, P161PfsX3, and M170IfsX1). These include one of the original patients reported by Dent and Friedman. Slit lamp examinations revealed early cataracts in only one boy with normal vision. None of these Dent 2 patients had metabolic acidosis; 3 had mild mental retardation. Analysis of all known OCRL1 mutations show that Dent 2 mutations fall into two classes that do not overlap with Lowe mutations. Bioinformatics analyses identified expressed OCRL1 splice variants that help explain the variability of those clinical features that distinguish Dent disease from Lowe syndrome. CONCLUSIONS: OCRL1 mutations can cause the renal phenotype of Dent disease, without acidosis or the dramatic eye abnormalities typical of Lowe syndrome. We propose a model to explain the phenotypic variability between Dent 2 and Lowe's based on distinctly different classes of mutations in OCRL1 producing splice variants.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".