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Query: UNIPROT:P06889 (Mol)
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A series of clonal cell lines were derived from rat liver epithelial cells after being infected with a defective retrovirus containing either v-raf (3611-MSV) or v-raf/v-myc(J2) together with a helper virus. These clones exhibited a different morphology from the regular cuboid shape of the control cells, infected only with the helper virus. All of the infected cell lines contained at least one full length copy of appropriate proviral DNA and expressed comparable levels of v-raf mRNA, although only the cells transformed with the v-raf/v-myc combination were capable of anchorage-independent growth in soft agar. All of the clones except the controls formed tumors in nude mice but with markedly different latency periods and growth rates. Thus, these cell lines represent an in vitro model for tumor progression. Two-dimensional polyacrylamide electrophoresis was used to investigate changes in cellular protein expression related to malignant conversion. The expression of three proteins of pI/Mr x 10(-3) 5.9-7.2/205 (RP1), 6.5-7.5/160 (RP2) and 4.0/85 (RP3) consistently matched the transformed phenotype. In particular the expression of RP1 and RP2 correlated with the relative tumorigenicity of the cell lines. Rat liver epithelial cell lines transformed by other protocols that did not involve v-raf also showed downregulation of these three polypeptides. Crude fractionation studies determined RP1 to be soluble and RP2 and RP3 to be membrane associated. RP2 was shown to be a glycoprotein containing mannose and galactose residues. These three proteins are consistent markers for the tumorigenic potential of rat liver epithelial cells.
Mol Carcinog 1990
PMID:Development of an in vitro model of tumor progression using v-raf and v-raf/v-myc transformed rat liver epithelial cells: correlation of tumorigenicity with the downregulation of specific proteins. 232 86

Microsatellites are widely recognised as providing a rich source of polymorphic markers for genetic mapping. Consequently, highly polymorphic CA repeats tightly linked to a disease locus are invaluable tools in linkage studies. We have developed an efficient technique for cloning microsatellite repeats from a region of interest contained within a yeast artificial chromosome (YAC). The YAC material is digested with a frequent cutting restriction endonuclease and ligated to polymerase chain reaction (PCR) amplifiable catch-linkers. A 5' biotinylated (CA)11 oligonucleotide is then used to select fragments containing a complementary repeat by binding to streptavidin-coated magnetic beads. The catch-linkers enable these fragments to be PCR amplified, cloned and sequenced. Primers are then designed to amplify the repeat locus and to confirm its genomic localization and heterozygosity. We have successfully used this technique to clone a new (CA)18 microsatellite from a 360-kb YAC. The YAC contains the CYBB locus in Xp21.1 and is thought to contain at least part of the RP3 gene responsible for X-linked retinitis pigmentosa. This new CA repeat is highly polymorphic with nine alleles identified so far and a heterozygosity of 0.75.
Mol Cell Probes 1995 Feb
PMID:A simple method for rapid isolation of microsatellites from yeast artificial chromosomes. 776 Aug 61

Long range physical mapping within the p21 region of the X chromosome identified a CpG rich island approximately 180 kb centromeric to the chronic granulomatous disease (CGD) locus. The segments adjacent to the CpG island hybridized to discrete bands in DNAs of several species and when used to screen retinal cDNA libraries led to the identification of cDNAs that detected a mRNA of 2.1 kb in many tissues. Molecular characterization of corresponding genomic clones of this novel human gene confirmed the origin of the cDNA clones and indicated a genomic structure with five exons spanning a total of 9 kb. The complete cDNA sequence revealed that this gene contained a putative open reading frame of 116 amino acids with a 3' untranslated region of 1.74 kb. The amino acid sequence shows a high degree of similarity to the predicted product of the tctex-1 gene of the mouse t complex. As linkage studies and patients with deletions have implicated the Xp21 region as containing the retinitis pigmentosa defect (RP3), the gene was assessed as a candidate disease gene in RP3 families. A single base pair polymorphism was identified within the coding region but no disease associated changes were found by single strand conformational polymorphism and sequencing analysis of amplified exons of 20 RP patients. Analysis of a dinucleotide repeat polymorphism within this gene in families affected with RP3 suggested refinement of the RP3 region.
Hum Mol Genet 1994 Feb
PMID:Identification of a gene from Xp21 with similarity to the tctex-1 gene of the murine t complex. 800 92

X-linked retinitis pigmentosa (XLRP) is characterized by retinal degeneration with night blindness and progressive reduction of the visual fields. By linkage and deletion analysis a gene locus (RP3) has been mapped to the short arm of the X chromosome between the genes CYBB and OTC. Analysis of transcript in this region has revealed a gene which is abundantly expressed in human retina and encodes a putative membrane protein with significant homologies to short consensus repeat (SCR/sushi) domains known from selections and complement proteins. The gene termed SRPX (sushi-repeat-containing protein, x chromosome) is deleted in an RP patient who also suffers from chronic granulomatous disease and McLeod syndrome. A 75 kb deletion removing exon 1 of the gene was also found in two brothers of a second XLRP family. However, no further functionally significant mutations were detected by SSCP screening of all 10 exons in 34 unrelated XLRP patients nor by full length RT-PCR sequencing in two RP3 families. The role of this highly conserved retinal gene in the pathogenesis of RP therefore remains to be determined.
Hum Mol Genet 1995 Dec
PMID:A gene (SRPX) encoding a sushi-repeat-containing protein is deleted in patients with X-linked retinitis pigmentosa. 863 8

A novel gene encoding a 2.2 kilobase transcript has been isolated from the Xp21.1 region of the human X chromosome by exon amplification. The gene, called EXT1, spans 80 kilobases and contains 12 exons, at least two of which are alternatively spliced and have predicted products of 464 and 471 amino acids respectively. Conceptual translation of the open reading frames shows one product with a 30 amino acid signal peptide, which is absent from the alternative transcript, followed by three complement control protein domains, a hydrophobic region with a possible role in membrane anchorage and short 17 amino acid putative cytoplasmic carboxyl terminus. An alternative first exon contains a 39 amino acid open reading frame which is rich in serine and threonine residues and contains a potential chondroitin/dermatan sulphate attachment site. Northern analysis showed ETX1 expression within the retina and heart with lower levels in several other tissues. Since ETX1 lies within the region thought to contain the x-linked retinitis pigmentosa (xIRP) gene, RP3, it was screened for mutation within a set of 45 xIRP patients using single strand conformation analysis and/or chemical cleavage of mismatch using reverse transcription/polymerase chain reaction amplification of polyA+RNA from blood cells. Three low frequently variants (17-23Ldel, P225S, S413F) were found in both patients and controls; one of which (P225S) was found in four of 45 unrelated patient chromosomes and one of 178 control chromosomes (p <0.001). The allelic association between P225S and xIRP alleles suggests a common ancestral chromosome bearing the P225S variant and an RP3 mutation at a neighbouring locus.
Hum Mol Genet 1995 Dec
PMID:Identification of a novel gene, ETX1 from Xp21.1, a candidate gene for X-linked retintis pigmentosa (RP3). 863 9

The gene for the most frequent from of X-linked retinitis pigmentosa (XLRP), RP3, has been assigned by genetic and physical mapping to a segment of less than 1000 kbp, which is flanked by the marker DXS1110 and the ornithine transcarbamylase (OTC) gene. In search of microdeletions, we have screened the DNA of 30 unrelated patients with XLRP by employing a representative set of YAC-derived DNA fragments that were generated by restriction enzyme digestion and PCR amplification. In one of these patients, a 6.4 kbp microdeletion was detected which was not present in the DNA of 444 male controls. A cosmid contig spanning the deletion was constructed and used to isolate cDNAs from retina-specific libraries. Exons corresponding to these expressed sequences as well as other putative exons were identified by sequencing more than 30 kbp of the critical region. So far, no point mutations in these putative exon sequences have been identified.
Hum Mol Genet 1996 Jun
PMID:Identification of a gene disrupted by a microdeletion in a patient with X-linked retinitis pigmentosa (XLRP). 877 99

X-linked retinitis pigmentosa (XLRP) is a genetically heterogeneous group of progressive retinal degenerations. The disease process is initiated by premature apoptosis of rod photoreceptor cells in the retina, which leads to reduced visual acuity and, eventually, complete blindness. Mutations in the retinitis pigmentosa GTPase regulator ( RPGR ), a ubiquitously expressed gene at the RP3 locus in Xp21.1, account for approximately 20% of all X-linked cases. We have analysed the expression of this gene by northern blot hybridization, cDNA library screening and RT-PCR in various organs from mouse and man. These studies revealed at least 12 alternatively spliced isoforms. Some of the transcripts are tissue specific and contain novel exons, which elongate or truncate the previously reported open reading frame of the mouse and human RPGR gene. One of the newly identified exons is expressed exclusively in the human retina and mouse eye and contains a premature stop codon. The deduced polypeptide lacks 169 amino acids from the C-terminus of the ubiquitously expressed variant, including an isoprenylation site. Moreover, this exon was found to be deleted in a family with XLRP. Our results indicate tissue-dependent regulation of alternative splicing of RPGR in mouse and man. The discovery of a retina-specific transcript may explain why phenotypic abberations in RP3 are confined to the eye.
Hum Mol Genet 1999 Aug
PMID:RPGR transcription studies in mouse and human tissues reveal a retina-specific isoform that is disrupted in a patient with X-linked retinitis pigmentosa. 1040 Oct 7

X-linked progressive retinal atrophy (XLPRA) in the Siberian husky dog is a naturally occurring X-linked retinopathy closely resembling X-linked retinitis pigmentosa (XLRP) in humans. In affected males, initial degeneration of rods is followed by cone degeneration and complete retinal atrophy; carrier females have random patches of rod degeneration consistent with random X chromosome inactivation. By typing the XLPRA pedigree with five intragenic markers [dystrophin, retinitis pigmentosa GTPase regulator ( RPGR ), tissue inhibitor of metalloproteinases 1, androgen receptor and factor IX], we established a linkage map of the canine X chromosome, and confirmed that the order of these five genes is identical to that on the human X. XLPRA was tightly linked to an intragenic RPGR polymorphism (LOD 11.7, zero recombination), thus confirming locus homology with RP3. We cloned the full-length canine RPGR cDNA and three additional splice variants. No disease-causing mutation was found in the RPGR-coding sequence of the four splice variants characterized, a finding similar to approximately 80% of human XLRP patients whose disease maps to the RP3 locus. In addition, there were no significant differences in the proportional expression of each splice variant in normal and pre-degenerate XLPRA-affected retina. Expression of all RPGR splice variants increased later in the disease, when retinas were undergoing active degeneration. The results provide further evidence of cross-species retention of a complex splicing pattern in the 3' portion of RPGR, the functional significance of which is unknown. In addition, the possibility of another disease locus in the RP3 region is supported.
Hum Mol Genet 2000 Mar 01
PMID:Mapping of X-linked progressive retinal atrophy (XLPRA), the canine homolog of retinitis pigmentosa 3 (RP3). 1069 76

A novel protein, called RPGRIP, has been identified as interacting with the RPGR protein, which is mutated in a severe form of human retinal degeneration, X-linked retinitis pigmentosa (RP3 type). The bovine RPGRIP was identified initially by screening for RPGR-interacting proteins with a bovine retina cDNA library using the yeast two-hybrid system. The specificity of the interaction was confirmed by co-immunoprecipitation of in vitro translated protein and using RPGR mutants. The human RPGRIP gene was isolated and shown to be expressed in retina and testis. Human RPGRIP spans a genomic interval of 34 kb, and consists of 15 exons, some of which are alternatively spliced. It was mapped using monochromosomal and radiation hybrid cell lines to chromosomal region 14q11. The function of RPGRIP is unknown; it shows no homology to proteins of known function, although it is predicted to form two coiled-coil domains at the N-terminus. RPGRIP is a strong candidate gene for causing human retinal degeneration.
Hum Mol Genet 2000 Sep 01
PMID:Identification of a novel protein interacting with RPGR. 1095 47

The canine disease, X-linked progressive retinal atrophy (XLPRA), is similar to human RP3, an X-linked form of retinitis pigmentosa, and maps to the same region in the X chromosome. Analysis of the physical map of the XLPRA and RP3 intervals shows a high degree of conservation in terms of genes and their order. We have found different mutations in exon ORF15 of the RPGR gene in two distinct mutant dog strains (XLPRA1, XLPRA2). Microdeletions resulting in a premature stop or a frameshift mutation result in very different retinal phenotypes, which are allele-specific and consistent for each mutation. The phenotype associated with the frameshift mutation in XLPRA2 is very severe and manifests during retinal development; the phenotype resulting from the XLPRA1 nonsense mutation is expressed only after normal photoreceptor morphogenesis. Splicing of RPGR mRNA transcripts in retina is complex, and either exon ORF15 or exon 19 can be a terminal exon. The retina-predominant transcript contains ORF15 as a terminal exon, and is expressed in normal and mutant retinas. The frameshift mutation dramatically alters the deduced amino acid sequence, and the protein aggregates in the endoplasmic reticulum of transfected cells. The cellular and molecular results in the two canine RPGR exon ORF15 mutations have implications for understanding the phenotypic variability found in human RP3 families that carry similar mutations.
Hum Mol Genet 2002 May 01
PMID:Different RPGR exon ORF15 mutations in Canids provide insights into photoreceptor cell degeneration. 1197 59


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