Autosomal recessive retinitis pigmentosa caused by mutations in the α subunit of rod cGMP phosphodiesterase

Huang, Sherleen H.; Pittler, Steven J.; Huang, Xiaodan; Oliveira, Luanne; Berson, Eliot L.; Dryja, Thaddeus P.

doi:10.1038/ng1295-468

Cited by 214 publications

(110 citation statements)

References 29 publications

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“…We have focused our studies on the PDE6A gene, which encodes the ␣-subunit of PDE6. Defects in the coding region of this gene account for a subset of autosomal recessive retinitis pigmentosa (4). Because all three genes that encode PDE6 subunits are required for subunit assembly (4 -6), the regulation of gene expression for each subunit could be essential to maximize enzyme production.…”

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confidence: 99%

Functional Analysis of the Rod Photoreceptor cGMP Phosphodiesterase α-Subunit Gene Promoter

Pittler

Zhang

Chen

et al. 2004

Journal of Biological Chemistry

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To understand the factors controlling expression of the cGMP phosphodiesterase type 6 (PDE6) genes, we have characterized the promoter of the human PDE6A gene that encodes the catalytic ␣-subunit. In vivo DNase I hypersensitivity assays revealed two sites immediately upstream of the PDE6A core promoter region. Transient transfection assay in Y79 cells of constructs containing varying lengths of the promoter region showed a decrease in promoter activity with increasing length. The most active segment contained a 177-bp upstream sequence including apparent Crx and Nrl transcription factor binding sites. Both Crx and Nrl transactivated the PDE6A promoter in HEK293 cells and showed a >100-fold increase when coexpressed. Coexpression of a dominant negative inhibitor of Nrl abolished Nrl transactivation but had no effect on Crx. DNase I footprinting assays identified three potential Crx binding sites within a 55-bp segment beginning 29 bp upstream of the transcription start point. Mutation of two of these sites reduced reporter gene activity by as much as 69%. Gel shifts showed that all three Crx sites required a TAAT sequence for efficient binding. Consistent with a requirement for Crx and Nrl in Pde6a promoter activity, Pde6a mRNA is reduced by 87% in the retina of Crx ؊/؊ mice and is undetectable in Nrl ؊/؊ mice at postnatal day 10. These results establish that both Nrl and Crx are required for full transcriptional activity of the PDE6A gene.

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Functional Analysis of the Rod Photoreceptor cGMP Phosphodiesterase α-Subunit Gene Promoter

Pittler

Zhang

Chen

et al. 2004

Journal of Biological Chemistry

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“…11,12 In contrast to these homozygous mutations in PDEB, a heterozygous missense mutation in PDEB is responsible for an autosomal dominant form of congenital stationary night blindness. 13 Another form of autosomal recessive retinitis pigmentosa is caused by mutations in the α subunit of the rod cGMP PDE (gene symbol PDEA), 14 which maps to 5q31.2-q34. 15 No mutations in the human γ and δ subunits have been thus far described.…”

Section: Introductionmentioning

confidence: 99%

Cloning and gene structure of the rod cGMP phosphodiesterase delta subunit gene (PDED) in man and mouse

et al. 1998

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Rod-specific cGMP phosphodiesterase (PDE) is a key enzyme of the phototransduction cascade, and mutations in its catalytic subunits have been associated with retinal degenerative diseases. The bovine δ-subunit solubilises the normally membrane-bound PDE and is the only subunit expressed in extraocular tissues. We isolated the human and mouse orthologs, and found 78% identity at the DNA level and 98% identity at the protein level. The Caenorhabditis elegans homolog shows 69% identity at the protein level. The human PDED gene consisted of 5 exons spanning at least 30 kb of genomic DNA. Northern blot analysis showed a 1.3 kb transcript in human retina, heart, brain, placenta, liver, and skeletal muscle. Fluorescence in situ hybridisation (FISH) and radiation hybrid mapping localised the human PDED gene to chromosome 2q37. A preliminary screen of all 5 exons in 20 unrelated patients with autosomal recessive retinitis pigmentosa revealed no PDED mutations.

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“…One of the most widely used models is the rd1 mouse, a model of rapidly progressive autosomal recessive RP due to a naturally occurring mutation in the b subunit of PDE6 (Bowes et al, 1990). Mutations in the b or a subunits of PDE6 cause human RP (McLaughlin et al, 1993;Huang et al, 1995) indicating that PDE6 function is critical for rod cell survival. Disruption of PDE6 activity leads to increased levels of cGMP, reduced closure of the cGMP-gated cation channel, and elevated levels of intracellular calcium.…”

Section: Photoreceptor Cell Death In Rpmentioning

confidence: 99%

Seeing the light: New insights into the molecular pathogenesis of retinal diseases

Campochiaro

2007

Journal Cellular Physiology

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In the past, most treatments for retinal diseases have been empirical. Steroids and/or laser photocoagulation and/or surgery have been tried for almost every condition with little or no understanding of the underlying disease. Over the past several years vision researchers have uncovered molecular components of processes, such as visual transduction and the visual cycle, that are critical for visual function, and identified other molecules that lead to dysfunction and disease processes such as neovascularization and macular edema. It is becoming clear that dysregulation of certain molecules can have major effects on retinal structure and function. Studies in animal models have suggested that inhibiting or augmenting levels of a single molecule can have major effects in complex disease processes. Although several molecules probably contribute to neovascularization and excessive vascular permeability in the eye, blockade of vascular endothelial growth factor (VEGF) has remarkable beneficial effects in animal models that have now been proven to apply to human diseases in clinical trials. Intraocular injection of VEGF antagonists has revolutionized the treatment of choroidal neovascularization (CNV) and macular edema and serves as a model of targeted ocular pharmacotherapy. Significant progress elucidating the molecular pathogenesis of several disease processes in the eye may soon lead to new treatments following the lead of VEGF antagonists. Initial treatments that provide benefit from frequent intraocular injections are likely to be followed by sustained delivery of drugs and/or prolonged protein delivery by gene transfer. The eye has entered the era of molecular therapy. J. Cell. Physiol. 213: 348–354, 2007. © 2007 Wiley‐Liss, Inc.

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Autosomal recessive retinitis pigmentosa caused by mutations in the α subunit of rod cGMP phosphodiesterase

Cited by 214 publications

References 29 publications

Functional Analysis of the Rod Photoreceptor cGMP Phosphodiesterase α-Subunit Gene Promoter

Functional Analysis of the Rod Photoreceptor cGMP Phosphodiesterase α-Subunit Gene Promoter

Cloning and gene structure of the rod cGMP phosphodiesterase delta subunit gene (PDED) in man and mouse

Seeing the light: New insights into the molecular pathogenesis of retinal diseases

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