Identification of IDH3G, encoding the gamma subunit of mitochondrial isocitrate dehydrogenase, as a novel candidate gene for X-linked retinitis pigmentosa
Bibliographic record
Abstract
PURPOSE: Retinitis pigmentosa (RP) is a genetically heterogeneous group of retinal degenerative disorders characterized by the loss of rod and cone photoreceptors, leading to visual impairment and blindness. To date, to our knowledge, X-linked RP has been associated with variants in 3 genes (RPGR, RP2, and OFD1), whereas genetic defects at 3 loci (RP6, RP24, and RP34) are yet unidentified. The aim of this study was to identify a novel candidate gene underlying X-linked RP. METHODS: Participants were identified from cohorts of genetically unsolved male individuals affected by RP, who underwent genome sequencing, exome sequencing, or candidate gene screening via direct Sanger sequencing at 3 referral centers. Specifically, 2 probands were identified at the National Reference Centre for Rare Retinal Diseases (Paris, France), 2 at the Massachusetts Eye and Ear Hospital (Boston, MA), and 1 at the National Reference Centre for Inherited Sensory Diseases (Montpellier, France). The pathogenicity of the identified variants was assessed using bioinformatic predictions, protein expression analyses, and mitochondrial function assays. RESULTS: We identified 4 rare single-nucleotide variants in IDH3G (HGNC:5386), located at the RP34 locus on the X chromosome, and a complete gene deletion, in 5 unrelated male individuals affected with nonsyndromic RP. The variants segregated with the phenotype in all available family members. In all cases, the disease severity was intermediate. None had high myopia. IDH3G encodes the γ subunit of mitochondrial isocitrate dehydrogenase (IDH3), an enzyme involved in the citric acid cycle, which is expressed in the inner segments of photoreceptors. Variants in IDH3A and IDH3B, encoding the other subunits of IDH3, have already been associated with nonsyndromic autosomal recessive RP. Bioinformatic predictions and functional assays support a pathogenic role for the variants identified in this study, possibly through partial loss of enzymatic activity and mitochondrial function. CONCLUSION: Our findings suggest that variants in IDH3G are a novel cause of X-linked RP.
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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 | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".