Home / Deep Research / RCBTB1-Related Retinopathy

RCBTB1-Related Retinopathy

1. Disease Information

2026-07-16
Falcon MONDO:0014955 Model: Edison Scientific Literature 19 citations

1. Disease Information

What is the disease?

RCBTB1-associated retinopathy is an IRD attributed to biallelic variants in RCBTB1 and characterized clinically by progressive macular chorioretinal atrophy with prominent RPE involvement, and in some cases an RP-like phenotype. (huang2023mitochondrialdysfunctionand pages 9-10, huang2023mitochondrialdysfunctionand pages 1-2)

Key identifiers

The retrieved corpus did not contain OMIM/Orphanet/MeSH/ICD/MONDO identifiers specifically for “RCBTB1-associated retinopathy” (evidence gap). (huang2023mitochondrialdysfunctionand pages 1-2)

However, the related vitreoretinopathy paper provides identifiers for disorders in which RCBTB1 haploinsufficiency was implicated: - FEVR: OMIM 133780, 305390, 605750, 601813, 613310, 616468 (wu2016haploinsufficiencyofrcbtb1 pages 1-2) - Coats disease: OMIM 300216 (wu2016haploinsufficiencyofrcbtb1 pages 1-2) - Related congenital vitreoretinopathies mentioned: persistent hyperplastic primary vitreous (OMIM 611308) and Norrie disease (OMIM 310600) (wu2016haploinsufficiencyofrcbtb1 pages 1-2)

Synonyms and alternative names

Evidence source types

2. Etiology

Disease causal factors

Risk factors

Protective factors and gene–environment interactions

Not identified in retrieved sources.

3. Phenotypes

Phenotype spectrum (human)

From a literature synthesis in a 2023 mechanistic study: - 15 cases from 11 families with biallelic RCBTB1 variants are described. (huang2023mitochondrialdysfunctionand pages 1-2) - Two main clinical patterns: 1) Progressive late-onset macular chorioretinal atrophy with peripheral retinal abnormalities presenting in the 40s–50s (11 cases from 9 families). (huang2023mitochondrialdysfunctionand pages 9-10) 2) Typical RP phenotype in the 20s (4 cases). (huang2023mitochondrialdysfunctionand pages 9-10) - Onset range for retinal atrophy (in nine families): 30–62 years. (huang2023mitochondrialdysfunctionand pages 9-10) - Common presentation: “gradually reduced visual acuity or visual distortion” from macular atrophy. (huang2023mitochondrialdysfunctionand pages 9-10)

Key ocular findings

Suggested HPO terms (mapping to retrieved descriptions)

Quality of life impact

Not quantified in the retrieved texts; progressive vision loss is implied. (huang2023mitochondrialdysfunctionand pages 9-10)

4. Genetic/Molecular Information

Causal gene

Pathogenic variants (explicitly retrieved)

Biallelic retinopathy-associated variants mentioned: - Compound heterozygous frameshifting variants c.170delG and c.707delA (reported as associated with progressive chorioretinal atrophy over 5 years in an earlier natural history description cited/recapped in 2023). (huang2023mitochondrialdysfunctionand pages 1-2)

Heterozygous LoF variants in vitreoretinopathy (FEVR/Coats) paper (important for gene function and variant interpretation): - NM_018191.3:c.707delA (p.Asn236Thrfs*11) (Coats disease case). (wu2016haploinsufficiencyofrcbtb1 pages 2-3) - NM_018191.3:c.1172+1G>A (p.Glu349Glyfs*17) (FEVR cases). (wu2016haploinsufficiencyofrcbtb1 pages 2-3)

Variant mechanism and inheritance

Modifier genes / epigenetic information / chromosomal abnormalities

Not identified in retrieved sources.

5. Environmental Information

No non-genetic environmental, lifestyle, or infectious contributors were identified in the retrieved sources.

6. Mechanism / Pathophysiology

RPE-centered oxidative stress and mitochondrial dysfunction axis (human cellular model; 2023)

Direct abstract quote supporting mechanism: “Patient-derived RPE cells displayed abnormal mitochondrial ultrastructure… increased levels of reactive oxygen species (ROS)… Control RPE upregulated RCBTB1 and NFE2L2… however, this response was highly attenuated in patient RPE… RCBTB1 was co-immunoprecipitated… by antibodies for either UBE2E3 or CUL3.” (huang2023mitochondrialdysfunctionand pages 1-2)

Key mechanistic findings (quantitative where available): - Mitochondrial dysfunction - Reduced mitochondrial membrane potential inferred from reduced MitoTracker signal (p = 0.0214). (huang2023mitochondrialdysfunctionand pages 5-6) - Ultrastructure abnormalities and increased damaged mitochondria; aberrant cristae 65.02 ± 12.41% (patient) vs 23.83 ± 3.23% (control). (huang2023mitochondrialdysfunctionand pages 5-6) - Oxidative stress dysregulation - Baseline ROS increased in patient iPSC-RPE (p = 0.015). (huang2023mitochondrialdysfunctionand pages 5-6) - Higher sensitivity to oxidative stress: significant ROS increase at 100 µM tBHP (p = 0.0463). (huang2023mitochondrialdysfunctionand pages 5-6) - Impaired NFE2L2/Nrf2 antioxidant response - NFE2L2 expression lower in untreated patient RPE (p = 0.0453) and fails to increase under tBHP, while control RPE upregulates NFE2L2 (e.g., p = 0.0437 at 100 µM; p = 0.0012 at 200 µM). (huang2023mitochondrialdysfunctionand pages 8-9) - NFE2L2 target genes (IDH1, SLC25A25, RXRA) reduced in patient RPE. (huang2023mitochondrialdysfunctionand pages 8-9) - Ubiquitination machinery interactions (CUL3/UBE2E3) - Co-immunoprecipitation shows RCBTB1 in complexes with CUL3 and UBE2E3; isoform-selective pull-down is described. (huang2023mitochondrialdysfunctionand pages 8-9) - An NFE2L2 antioxidant response element motif (TGACCCGGC) is noted upstream of RCBTB1 transcription start site, suggesting NFE2L2-regulated induction. (huang2023mitochondrialdysfunctionand pages 10-12)

Author interpretation (expert opinion): The authors conclude that their results “highlight RPE mitochondria as a key target site in the pathogenesis of RCBTB1-associated retinopathy” and suggest that therapies alleviating mitochondrial dysfunction may be useful. (huang2023mitochondrialdysfunctionand pages 10-12)

Retinal angiogenesis axis (heterozygous LoF vitreoretinopathies; 2016)

Wu et al. provide mechanistic evidence linking reduced RCBTB1 to Norrin/FZD4/LRP5 β-catenin signaling and angiogenesis: - RCBTB1 knockdown reduces β-catenin nuclear accumulation and reduces Norrin-induced TCF/LEF reporter activity (reported reductions to approximately 50% and 33% at different ligand doses in evidence synthesis). (wu2016haploinsufficiencyofrcbtb1 pages 3-6) - Zebrafish rcbtb1 knockdown causes vascular anomalies in intersegmental and intraocular vessels. (wu2016haploinsufficiencyofrcbtb1 pages 1-2, wu2016haploinsufficiencyofrcbtb1 pages 6-7)

Suggested GO (process), CL (cell type), and tissue terms

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

Inheritance

Epidemiology and population genetics

  • Prevalence/incidence, carrier frequency, and founder effects are not available in the retrieved corpus (evidence gap).

10. Diagnostics

Clinical imaging and tests (disease-specific)

Genetic testing and real-world implementation

  • Whole-exome sequencing used to identify RCBTB1 variants in vitreoretinopathy pedigrees; confirmatory direct sequencing and RT-PCR/amplicon sequencing used to verify splice effects. (wu2016haploinsufficiencyofrcbtb1 pages 2-3)
  • Copy-number analysis (CNVs): arrEYE array CGH platform designed for retinal dystrophy genes including RCBTB1; includes qPCR validation and Sanger sequencing of exons/splice boundaries. (cauwenbergh2017arreyeacustomized pages 2-4)

Broader IRD diagnostic yield benchmarks (helpful for clinical implementation)

Differential diagnosis

Not specified for RCBTB1 macular chorioretinal atrophy in retrieved sources (evidence gap).

11. Outcome/Prognosis

Quantitative prognosis (VA trajectories, blindness rates) is not provided in retrieved sources; progressive enlargement of atrophic lesions is described. (huang2023mitochondrialdysfunctionand pages 9-10)

12. Treatment

Current applications / real-world implementations

Disease-specific management for RCBTB1-retinopathy is not detailed in retrieved sources.

For related Coats disease case, surgical/medical retinal detachment management is described: cryopexy, pars plana vitrectomy, removal of subretinal fibrous cord, and encircling buckle. (wu2016haploinsufficiencyofrcbtb1 pages 2-3)

Experimental / mechanism-based approaches

Authors propose that therapeutic approaches aimed at alleviating mitochondrial dysfunction may be useful, based on similarity to severe mitochondrial retinopathy and observed mitochondrial pathology. (huang2023mitochondrialdysfunctionand pages 10-12)

Clinical trials

No RCBTB1-targeted clinical trials were retrieved. Gene therapy trials retrieved were RPE65-focused (e.g., LX101) and are not directly applicable to RCBTB1. (NCT06212297 chunk 1, NCT07054632 chunk 1)

13. Prevention

Not described in retrieved sources; general genetic counseling and cascade testing are implied by Mendelian genetics but not explicitly detailed.

14. Other Species / Natural Disease

Not identified in retrieved sources.

15. Model Organisms

Recent developments prioritized (2023–2024)

2023 mechanistic disease modeling (Cells)

2023 clinical implementation context (Genes)

Visual evidence (mechanistic)

Figures extracted from the 2023 iPSC-RPE study show mitochondrial ultrastructural abnormalities and reduced MitoTracker labeling in patient-derived RPE. (huang2023mitochondrialdysfunctionand media 84d6e22c, huang2023mitochondrialdysfunctionand media 34d1da4f)

Evidence gaps (explicit)

  • Disease-specific OMIM/Orphanet/MONDO/MeSH/ICD identifiers for RCBTB1-associated retinopathy were not present in retrieved texts.
  • Epidemiology (prevalence/incidence), gnomAD carrier frequency, founder variants, and penetrance estimates specific to retinopathy were not retrieved.
  • No RCBTB1-specific therapeutic trials were retrieved.
  • Differential diagnosis lists and formal diagnostic criteria for the macular chorioretinal atrophy phenotype were not retrieved.

Key primary sources (with dates/URLs where present in retrieved texts)

References

  1. (huang2023mitochondrialdysfunctionand pages 9-10): Zhiqin Huang, Dan Zhang, Shang-Chih Chen, Di Huang, David Mackey, Fred K. Chen, and Samuel McLenachan. Mitochondrial dysfunction and impaired antioxidant responses in retinal pigment epithelial cells derived from a patient with rcbtb1-associated retinopathy. Cells, 12:1358, May 2023. URL: https://doi.org/10.3390/cells12101358, doi:10.3390/cells12101358. This article has 9 citations.

  2. (huang2023mitochondrialdysfunctionand pages 1-2): Zhiqin Huang, Dan Zhang, Shang-Chih Chen, Di Huang, David Mackey, Fred K. Chen, and Samuel McLenachan. Mitochondrial dysfunction and impaired antioxidant responses in retinal pigment epithelial cells derived from a patient with rcbtb1-associated retinopathy. Cells, 12:1358, May 2023. URL: https://doi.org/10.3390/cells12101358, doi:10.3390/cells12101358. This article has 9 citations.

  3. (wu2016haploinsufficiencyofrcbtb1 pages 2-3): Jeng-Hung Wu, Jorn-Hon Liu, Yu-Chieh Ko, Chi-Tang Wang, Yu-Chien Chung, Kuo-Chang Chu, Tze-Tze Liu, Hsiao-Ming Chao, Yun-Jin Jiang, Shih-Jen Chen, and Ming-Yi Chung. Haploinsufficiency of rcbtb1 is associated with coats disease and familial exudative vitreoretinopathy. Human molecular genetics, 25 8:1637-47, Apr 2016. URL: https://doi.org/10.1093/hmg/ddw041, doi:10.1093/hmg/ddw041. This article has 75 citations and is from a domain leading peer-reviewed journal.

  4. (wu2016haploinsufficiencyofrcbtb1 pages 3-6): Jeng-Hung Wu, Jorn-Hon Liu, Yu-Chieh Ko, Chi-Tang Wang, Yu-Chien Chung, Kuo-Chang Chu, Tze-Tze Liu, Hsiao-Ming Chao, Yun-Jin Jiang, Shih-Jen Chen, and Ming-Yi Chung. Haploinsufficiency of rcbtb1 is associated with coats disease and familial exudative vitreoretinopathy. Human molecular genetics, 25 8:1637-47, Apr 2016. URL: https://doi.org/10.1093/hmg/ddw041, doi:10.1093/hmg/ddw041. This article has 75 citations and is from a domain leading peer-reviewed journal.

  5. (huang2023mitochondrialdysfunctionand pages 8-9): Zhiqin Huang, Dan Zhang, Shang-Chih Chen, Di Huang, David Mackey, Fred K. Chen, and Samuel McLenachan. Mitochondrial dysfunction and impaired antioxidant responses in retinal pigment epithelial cells derived from a patient with rcbtb1-associated retinopathy. Cells, 12:1358, May 2023. URL: https://doi.org/10.3390/cells12101358, doi:10.3390/cells12101358. This article has 9 citations.

  6. (huang2023mitochondrialdysfunctionand pages 10-12): Zhiqin Huang, Dan Zhang, Shang-Chih Chen, Di Huang, David Mackey, Fred K. Chen, and Samuel McLenachan. Mitochondrial dysfunction and impaired antioxidant responses in retinal pigment epithelial cells derived from a patient with rcbtb1-associated retinopathy. Cells, 12:1358, May 2023. URL: https://doi.org/10.3390/cells12101358, doi:10.3390/cells12101358. This article has 9 citations.

  7. (wu2016haploinsufficiencyofrcbtb1 pages 1-2): Jeng-Hung Wu, Jorn-Hon Liu, Yu-Chieh Ko, Chi-Tang Wang, Yu-Chien Chung, Kuo-Chang Chu, Tze-Tze Liu, Hsiao-Ming Chao, Yun-Jin Jiang, Shih-Jen Chen, and Ming-Yi Chung. Haploinsufficiency of rcbtb1 is associated with coats disease and familial exudative vitreoretinopathy. Human molecular genetics, 25 8:1637-47, Apr 2016. URL: https://doi.org/10.1093/hmg/ddw041, doi:10.1093/hmg/ddw041. This article has 75 citations and is from a domain leading peer-reviewed journal.

  8. (huang2023mitochondrialdysfunctionand pages 5-6): Zhiqin Huang, Dan Zhang, Shang-Chih Chen, Di Huang, David Mackey, Fred K. Chen, and Samuel McLenachan. Mitochondrial dysfunction and impaired antioxidant responses in retinal pigment epithelial cells derived from a patient with rcbtb1-associated retinopathy. Cells, 12:1358, May 2023. URL: https://doi.org/10.3390/cells12101358, doi:10.3390/cells12101358. This article has 9 citations.

  9. (wu2016haploinsufficiencyofrcbtb1 pages 6-7): Jeng-Hung Wu, Jorn-Hon Liu, Yu-Chieh Ko, Chi-Tang Wang, Yu-Chien Chung, Kuo-Chang Chu, Tze-Tze Liu, Hsiao-Ming Chao, Yun-Jin Jiang, Shih-Jen Chen, and Ming-Yi Chung. Haploinsufficiency of rcbtb1 is associated with coats disease and familial exudative vitreoretinopathy. Human molecular genetics, 25 8:1637-47, Apr 2016. URL: https://doi.org/10.1093/hmg/ddw041, doi:10.1093/hmg/ddw041. This article has 75 citations and is from a domain leading peer-reviewed journal.

  10. (cauwenbergh2017arreyeacustomized pages 2-4): Caroline Van Cauwenbergh, Kristof Van Schil, Robrecht Cannoodt, Miriam Bauwens, Thalia Van Laethem, Sarah De Jaegere, Wouter Steyaert, Tom Sante, Björn Menten, Bart P. Leroy, Frauke Coppieters, and Elfride De Baere. Arreye: a customized platform for high-resolution copy number analysis of coding and noncoding regions of known and candidate retinal dystrophy genes and retinal noncoding rnas. Genetics in Medicine, 19:457-466, Apr 2017. URL: https://doi.org/10.1038/gim.2016.119, doi:10.1038/gim.2016.119. This article has 57 citations and is from a highest quality peer-reviewed journal.

  11. (areblom2023adescriptionof pages 1-2): Maria Areblom, Sten Kjellström, Sten Andréasson, Anders Öhberg, Lotta Gränse, and Ulrika Kjellström. A description of the yield of genetic reinvestigation in patients with inherited retinal dystrophies and previous inconclusive genetic testing. Genes, 14:1413, Jul 2023. URL: https://doi.org/10.3390/genes14071413, doi:10.3390/genes14071413. This article has 8 citations.

  12. (panneman2022costeffectivesequenceanalysis pages 1-3): Daan M. Panneman, Rebekkah J. Hitti-Malin, Lara K. Holtes, Suzanne E. de Bruijn, Janine Reurink, Erica G. M. Boonen, Muhammad Imran Khan, Manir Ali, Sten Andréasson, Elfride De Baere, Sandro Banfi, Miriam Bauwens, Tamar Ben-Yosef, Béatrice Bocquet, Marieke De Bruyne, Berta de la Cerda, Frauke Coppieters, Pietro Farinelli, Thomas Guignard, Chris F. Inglehearn, Marianthi Karali, Ulrika Kjellström, Robert Koenekoop, Bart de Koning, Bart P. Leroy, Martin McKibbin, Isabelle Meunier, Konstantinos Nikopoulos, Koji M. Nishiguchi, James A. Poulter, Carlo Rivolta, Enrique Rodríguez de la Rúa, Patrick Saunders, Francesca Simonelli, Yasmin Tatour, Francesco Testa, Alberta A. H. J. Thiadens, Carmel Toomes, Anna M. Tracewska, Hoai Viet Tran, Hiroaki Ushida, Veronika Vaclavik, Virginie J. M. Verhoeven, Maartje van de Vorst, Christian Gilissen, Alexander Hoischen, Frans P. M. Cremers, and Susanne Roosing. Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and leber congenital amaurosis. Frontiers in Cell and Developmental Biology, Feb 2023. URL: https://doi.org/10.3389/fcell.2023.1112270, doi:10.3389/fcell.2023.1112270. This article has 34 citations.

  13. (NCT06212297 chunk 1): Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy. Innostellar Biotherapeutics Co.,Ltd. 2023. ClinicalTrials.gov Identifier: NCT06212297

  14. (NCT07054632 chunk 1): Efficacy and Safety of LX101 for Inherited Retinal Dystrophy Associated With RPE65 Mutations. Innostellar Biotherapeutics Co.,Ltd. 2023. ClinicalTrials.gov Identifier: NCT07054632

  15. (huang2023mitochondrialdysfunctionand media 84d6e22c): Zhiqin Huang, Dan Zhang, Shang-Chih Chen, Di Huang, David Mackey, Fred K. Chen, and Samuel McLenachan. Mitochondrial dysfunction and impaired antioxidant responses in retinal pigment epithelial cells derived from a patient with rcbtb1-associated retinopathy. Cells, 12:1358, May 2023. URL: https://doi.org/10.3390/cells12101358, doi:10.3390/cells12101358. This article has 9 citations.

  16. (huang2023mitochondrialdysfunctionand media 34d1da4f): Zhiqin Huang, Dan Zhang, Shang-Chih Chen, Di Huang, David Mackey, Fred K. Chen, and Samuel McLenachan. Mitochondrial dysfunction and impaired antioxidant responses in retinal pigment epithelial cells derived from a patient with rcbtb1-associated retinopathy. Cells, 12:1358, May 2023. URL: https://doi.org/10.3390/cells12101358, doi:10.3390/cells12101358. This article has 9 citations.

Artifacts

## Context ID: pqac-00000013 The document does not contain a figure or table summarizing the clinical features or imaging findings of RCBTB1-associated retinopa ## Context ID: pqac-00000015 I have extracted Figure 1 (TEM mitochondrial abnormalities) and Figure 2 (MitoTracker assay) along with their respective legends. F