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Mai M Abd El-Aziz,
Isabel Barragan,
Ciara A O'Driscoll,
Leo Goodstadt,
Elena Prigmore,
Salud Borrego,
Marcela Mena,
Juan I Pieras,
Mohamed F El-Ashry,
Leen Abu Safieh,
Amna Shah,
Michael E Cheetham,
Nigel P Carter, Christina Chakarova,
Chris P Ponting,
Shomi S Bhattacharya,
Guillermo Antinolo
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ABSTRACT: Using a positional cloning approach supported by comparative genomics, we have identified a previously unreported gene, EYS, at the RP25 locus on chromosome 6q12 commonly mutated in autosomal recessive retinitis pigmentosa. Spanning over 2 Mb, this is the largest eye-specific gene identified so far. EYS is independently disrupted in four other mammalian lineages, including that of rodents, but is well conserved from Drosophila to man and is likely to have a role in the modeling of retinal architecture.
Nature Genetics 11/2008; 40(11):1285-7. · 35.53 Impact Factor
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ABSTRACT: PRPF3 is an element of the splicing machinery ubiquitously expressed, yet mutations in this gene are associated with a tissue-specific phenotype: autosomal dominant retinitis pigmentosa (RP). Here, we studied the subcellular localization of endogenous- and mutant-transfected PRPF3. We found that (i) subcellular distribution of the endogenous wild-type protein co-localizes with small nuclear ribonucleoproteins, partially with a nucleolar marker and accumulates in speckles labeled by SC35; (ii) in human retinas, PRPF3 does not show a distinctive abundance in photoreceptors, the cells affected in RP and (iii) the RP causing mutant PRPF3, differently from the wild-type protein, forms abnormally big aggregates in transfected photoreceptor cells. Aggregation of T494M mutant PRPF3 inside the nucleus triggers apoptosis only in photoreceptor cells. On the basis of the observation that mutant PRPF3 accumulates in the nucleolus and that transcriptional, translational and proteasome inhibition can induce this phenomenon in non-photoreceptor cells, we hypothesize that mutation affects splicing factor recycling. Noteworthy, accumulation of the mutant protein in big aggregates also affects distribution of some other splicing factors. Our data suggest that the mutant protein has a cell-specific dominant effect in rod photoreceptors while appears not to be harmful to epithelial and fibroblast cells.
Human Molecular Genetics 08/2007; 16(14):1699-707. · 7.64 Impact Factor
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James S Friedman,
Bo Chang,
Chitra Kannabiran, Christina Chakarova,
Hardeep P Singh,
Subhadra Jalali,
Norman L Hawes,
Kari Branham,
Mohammad Othman,
Elena Filippova,
Debra A Thompson,
Andrew R Webster,
Sten Andréasson,
Samuel G Jacobson,
Shomi S Bhattacharya,
John R Heckenlively,
Anand Swaroop
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ABSTRACT: The rd3 mouse is one of the oldest identified models of early-onset retinal degeneration. Using the positional candidate approach, we have identified a C-->T substitution in a novel gene, Rd3, that encodes an evolutionarily conserved protein of 195 amino acids. The rd3 mutation results in a predicted stop codon after residue 106. This change is observed in four rd3 lines derived from the original collected mice but not in the nine wild-type mouse strains that were examined. Rd3 is preferentially expressed in the retina and exhibits increasing expression through early postnatal development. In transiently transfected COS-1 cells, the RD3-fusion protein shows subnuclear localization adjacent to promyelocytic leukemia-gene-product bodies. The truncated mutant RD3 protein is detectable in COS-1 cells but appears to get degraded rapidly. To explore potential association of the human RD3 gene at chromosome 1q32 with retinopathies, we performed a mutation screen of 881 probands from North America, India, and Europe. In addition to several alterations of uncertain significance, we identified a homozygous alteration in the invariant G nucleotide of the RD3 exon 2 donor splice site in two siblings with Leber congenital amaurosis. This mutation is predicted to result in premature truncation of the RD3 protein, segregates with the disease, and is not detected in 121 ethnically matched control individuals. We suggest that the retinopathy-associated RD3 protein is part of subnuclear protein complexes involved in diverse processes, such as transcription and splicing.
The American Journal of Human Genetics 12/2006; 79(6):1059-70. · 10.60 Impact Factor
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Zhenglin Yang,
Bernardo V Alvarez, Christina Chakarova,
Li Jiang,
Goutam Karan,
Jeanne M Frederick,
Yu Zhao,
Yves Sauvé,
Xi Li,
Eberhart Zrenner,
Bernd Wissinger,
Anneke I Den Hollander,
Bradley Katz,
Wolfgang Baehr,
Frans P Cremers,
Joseph R Casey,
Shomi S Bhattacharya,
Kang Zhang
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ABSTRACT: Retina and retinal pigment epithelium (RPE) belong to the metabolically most active tissues in the human body. Efficient removal of acid load from retina and RPE is a critical function mediated by the choriocapillaris. However, the mechanism by which pH homeostasis is maintained is largely unknown. Here, we show that a functional complex of carbonic anhydrase 4 (CA4) and Na+/bicarbonate co-transporter 1 (NBC1) is specifically expressed in the choriocapillaris and that missense mutations in CA4 linked to autosomal dominant rod-cone dystrophy disrupt NBC1-mediated HCO3- transport. Our results identify a novel pathogenic pathway in which a defect in a functional complex involved in maintaining pH balances, but not expressed in retina or RPE, leads to photoreceptor degeneration. The importance of a functional CA4 for survival of photoreceptors implies that CA inhibitors, which are widely used as medications, particularly in the treatment of glaucoma, may have long-term adverse effects on vision.
Human Molecular Genetics 02/2005; 14(2):255-65. · 7.64 Impact Factor
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Mai M Abd El-Aziz,
Isabel Barragán,
Ciara A O'Driscoll,
Leo Goodstadt,
Elena Prigmore,
Salud Borrego,
Marcela Mena,
Juan I Pieras,
Mohamed F El-Ashry,
Leen Abu-Safieh,
Amna Shah,
Michael E Cheetham,
Nigel P Carter, Christina Chakarova,
Chris P Ponting,
Shomi S Bhattacharya,
Guillermo Antiñolo
[show abstract]
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ABSTRACT: 3 pages, 2 figures, 1 table.-- PMID: 18836446 [PubMed].-- Supporting information (Suppl. Methods, Suppl. Note, Suppl. Figs 1–4, Suppl. Table 1) available at: http://www.nature.com/ng/journal/v40/n11/suppinfo/ng.241_S1.html Using a positional cloning approach supported by comparative genomics, we have identified a previously unreported gene, EYS, at the RP25 locus on chromosome 6q12 commonly mutated in autosomal recessive retinitis pigmentosa. Spanning over 2 Mb, this is the largest eye-specific gene identified so far. EYS is independently disrupted in four other mammalian lineages, including that of rodents, but is well conserved from Drosophila to man and is likely to have a role in the modeling of retinal architecture. This study was funded by Fondo de Investigación Sanitaria (PI050857), Spain; Consejería de Salud (PI-0334/2007), Junta de Andalucía, Spain; British Retinitis Pigmentosa Society (grant ref. GR556); Foresight, Dubai; Foundation Fighting Blindness (USA); National Institute of Health Research Biomedical Research Centre for Ophthalmology, The Special Trustees of Moorfields Eye Hospital London; the UK Medical Research Council and EU-Neurotrain (grant ref. MEST-CT-2005-020235); EU-GENORET (grant ref. LSHG-CT-2005-512036). The Centro de Investigación Biomédica en Red de Enfermedades Raras is an initiative of the Instituto de Salud Carlos III. N.P.C. and E.P. were supported by the Wellcome Trust. Peer reviewed
