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

Lorenz, Bettina; Migliaccio, Carmela; Lichtner, Peter; Meyer, Carsten; Strom, Tim M.; D’Urso, Michele; Becker, Jörg; Ciccodicola, Alfredo; Meitinger, Thomas

doi:10.1038/sj.ejhg.5200215

Cited by 15 publications

(13 citation statements)

References 21 publications

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“…Recently, studies to identify proteins that interact with RPGR, showed that the RCC1-like domain of RPGR interacts with phosphodiesterase delta subunit. 29 This interaction links RPGR to the visual transduction cascade that regulates the rod phosphodiesterase holoenzyme, 30 though no specific related activity (eg of guanine nucleotide exchange) has been identified. The large group of XLRP families in which no mutations have been detected in RPGR provide one starting point for the study of interacting proteins or additional mutations that regulate RPGR.…”

Section: Discussionmentioning

confidence: 99%

Mutation analysis of the RPGR gene reveals novel mutations in south European patients with X-linked retinitis pigmentosa

et al. 1999

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The RPGR (retinitis pigmentosa GTPase regulator) gene has been shown to be mutated in 10-20% of patients with X-linked retinitis pigmentosa (XLRP), a severe form of inherited progressive retinal degeneration. A total of 29 different RPGR mutations have been identified in northern European and United States patients. We have performed mutation analysis of the RPGR gene in a cohort of 49 southern European males affected with XLRP. By multiplex SSCA and automatic direct sequencing of all 19 RPGR exons, seven different and novel mutations were identified in eight of the 49 families; these include three splice site mutations, two microdeletions, and two missense mutations. RNA analysis showed that the three splice site defects resulted in the generation of aberrant RPGR transcripts. Six of these mutations were detected in the conserved amino-terminal region of RPGR protein, containing tandem repeats homologous to the RCC1 protein, a guanine nucleotide-exchange factor for RanGTPase. Several exonic and intronic sequence variations were also detected. None of the RPGR mutations reported in other populations were identified in our series. Our results are consistent with the notions of heterogeneity and minority causation of XLRP by mutations in RPGR in Caucasian populations.

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Section: Discussionmentioning

confidence: 99%

Mutation analysis of the RPGR gene reveals novel mutations in south European patients with X-linked retinitis pigmentosa

et al. 1999

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“…Extrapolated to humans carrying two PDE6D null alleles, the slow progression predicts a phenotype resembling a recessive cone/rod dystrophy. To date, no retina or macular dystrophy has been linked to the human PDE6D gene located on chromosome 2q35-37 (24,25).…”

Section: Increased Sensitivity Of Pde6d ؊/؊ Rod Photoreceptors In Sinmentioning

confidence: 99%

Deletion of PrBP/δ impedes transport of GRK1 and PDE6 catalytic subunits to photoreceptor outer segments

Zhang

Doan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The mouse Pde6d gene encodes a ubiquitous prenyl binding protein, termed PrBP/␦, of largely unknown physiological function. PrBP/␦ was originally identified as a putative rod cGMP phosphodiesterase (PDE6) subunit in the retina, where it is relatively abundant. To investigate the consequences of Pde6d deletion in retina, we generated a Pde6d ؊/؊ mouse by targeted recombination. Although manifesting reduced body weight, the Pde6d ؊/؊ mouse was viable and fertile and its retina developed normally. Immunocytochemistry showed that farnesylated rhodopsin kinase (GRK1) and prenylated rod PDE6 catalytic subunits partially mislocalized in Pde6d ؊/؊ rods, whereas rhodopsin was unaffected. In Pde6d ؊/؊ rod single-cell recordings, sensitivity to single photons was increased and saturating flash responses were prolonged. Pde6d ؊/؊ scotopic paired-flash electroretinograms indicated a delay in recovery of the dark state, likely due to reduced levels of GRK1 in rod outer segments. In Pde6d ؊/؊ cone outer segments, GRK1 and cone PDE6␣ were present at very low levels and the photopic b-wave amplitudes were reduced by 70%. Thus the absence of PrBP/␦ in retina impairs transport of prenylated proteins, particularly GRK1 and cone PDE, to rod and cone outer segments, resulting in altered photoreceptor physiology and a phenotype of a slowly progressing rod/cone dystrophy.prenyl binding protein ͉ rod/cone dystrophy ͉ vesicular transport ͉ isoprenylation ͉ membrane association

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“…7). The ␤-galactosidase activity, the parameter for protein-protein interaction, was detected as described (18 (3,26) and is greatly enhanced in retina (A.W., unpublished work). Together with the high affinity, we conclude that the RLDs of RPGR and PDE␦ are likely to be genuine binding partners.…”

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confidence: 99%

The retinitis pigmentosa GTPase regulator, RPGR, interacts with the delta subunit of rod cyclic GMP phosphodiesterase

Linari

Ueffing

Manson

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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110

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Recently, the retinitis pigmentosa 3 (RP3) gene has been cloned and named retinitis pigmentosa GTPase regulator (RPGR). The amino-terminal half of RPGR is homologous to regulator of chromosome condensation (RCC1), the nucleotide exchange factor for the small GTPbinding protein Ran. In a yeast two-hybrid screen we identified the delta subunit of rod cyclic GMP phosphodiesterase (PDE␦) as interacting with the RCC1-like domain (RLD) of RPGR (RPGR 392 ). The interaction of RPGR with PDE␦ was confirmed by pull-down assays and plasmon surface resonance. The binding affinity was determined to be 90 nM. Six missense mutations at evolutionary conserved residues within the RLD, which were found in RP3 patients, were analyzed by using the two-hybrid system. All missense mutations showed reduced interaction with PDE␦. A non-RP3-associated missense substitution outside the RLD, V36F, did not abolish the interaction with PDE␦. PDE␦ is widely expressed and highly conserved across evolution and is proposed to regulate the membrane insertion or solubilization of prenylated proteins, including the catalytic subunits of the PDE holoenzyme involved in phototransduction and small GTP-binding proteins of the Rab family. These results suggest that RPGR mutations give rise to retinal degeneration by dysregulation of intracellular processes that determine protein localization and protein transport.Retinitis pigmentosa (RP) designates a heterogeneous group of hereditary retinal dystrophies characterized by impaired dark adaptation, progressive visual field defects, and severe reduction in visual acuity. X-linked RP (xlRP) is the most severe form of RP, which affects about 1 in 25,000 and leads to blindness by the third or fourth decade (1). Clinical surveys indicate that at least 16-33% of all RP patients show X-linked inheritance (2). The most common form of xlRP is RP type 3 (RP3), which affects about 70% of xlRP patients and is caused by mutations in a gene named RPGR.The RP GTPase regulator (RPGR) gene codes for a 90-kDa protein that contains a weakly conserved nucleotide binding motif at the N terminus and a potential isoprenylation site at the carboxyl terminus (3). Most significantly, the N-terminal half of RPGR is homologous to the regulator of chromosome condensation (RCC1) (3, 4). RCC1 is a chromatin binding protein that is involved in cell cycle regulation. Biochemically, RCC1 is the guanine nucleotide exchange factor (GEF) for Ran (5, 6), a small GTP-binding protein that is essential for nucleo-cytoplasmic transport (7,8). Recently, the threedimensional structure of RCC1 has been determined (9). It consists of a seven-bladed propeller formed by internal repeats. This structural motif also is found in p532, a GEF for Rab and Arf proteins (10), indicating that RCC1-like proteins might be general guanine nucleotide exchange proteins. To investigate the role of the RCC1-like domain (RLD) of RPGR in RP3, we applied the yeast two-hybrid system to identify proteins interacting with the RLD of RPGR. We were able to identify t...

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

Cited by 15 publications

References 21 publications

Mutation analysis of the RPGR gene reveals novel mutations in south European patients with X-linked retinitis pigmentosa

Mutation analysis of the RPGR gene reveals novel mutations in south European patients with X-linked retinitis pigmentosa

Deletion of PrBP/δ impedes transport of GRK1 and PDE6 catalytic subunits to photoreceptor outer segments

The retinitis pigmentosa GTPase regulator, RPGR, interacts with the delta subunit of rod cyclic GMP phosphodiesterase

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