Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa

Vervoort, Raf; Lennon, Alan; Bird, Alan C.; Tulloch, B.; Axton, Richard; Miano, Maria Giuseppina; Meindl, Alfons; Meitinger, Thomas; Ciccodicola, Alfredo; Wright, Alan F.

doi:10.1038/78182

Cited by 374 publications

(471 citation statements)

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“…Possible explanations include the expression of a retina-specific transcript [Kirschner et al, 1999;Vervoort et al, 2000], and/or a role in a retinaspecific pathway [Roepman et al, 2000;Hong et al, 2000Hong et al, , 2001. A puzzling observation is the relatively low level of RPGR transcripts found in the retina in human [Meindl et al, 1996], mouse [Kirschner et al, 1999], and dog [Zeiss et al, 2000] suggesting a retina-specific regulation of RPGR mRNA levels.…”

Section: Retina-specific Phenotypementioning

confidence: 90%

“…The argument can also be reversed: the presence of mutations in skipped exons indicates that the alternative products do not have residual function. In the case of RPGR, mutations have been found in exons 14 and 15, indicating that they do not have redundant functions and that transcripts lacking these exons [Kirschner et al, 1999;Vervoort et al, 2000] are insufficient for the normal function of RPGR in the retina.…”

Section: Mutations and Alternative Splicingmentioning

confidence: 99%

“…Most likely this is not due to sample size factors: over 380 patients for Table 3 for details). [Kirschner et al, 1999;Sharon et al, 2000;Zito et al, 2000a;Vervoort et al, 2000], 70 for exon ORF14 [Kirschner et al, 1999;, and 47 for exon 15b1 and 15b2 . In view of this lack of mutations it seems unlikely that exons ORF14, 15a, 15b1, 15b2, and 16 19 are necessary for normal function in the retina.…”

Section: Foundmentioning

confidence: 99%

“…The vast majority of mutations in RPGR in British XLRP patients are localized in an alternative 3′ terminal exon, called exon ORF15 [see Vervoort et al, 2000] (Table 1). The proportion of mutations identified in RPGR in this population now agrees with that predicted by linkage analysis.…”

Section: Mutation Screening Of Exon Orf15mentioning

confidence: 99%

“…These 19 exons however, harbor only 11 to 27% of XLRP mutations, which is much less than expected from linkage analysis. Transcriptional studies have revealed extensive alternative splicing of RPGR in mouse [Yan et al, 1998;Kirschner et al, 1999], dog [Zeiss et al, 2000], and human [Kirschner et al, 1999;Vervoort et al, 2000] tissues. Alternatively spliced human RPGR exons are shown in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

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Mutations ofRPGR in X-linked retinitis pigmentosa (RP3)

Vervoort

Wright

2002

Hum. Mutat.

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Mutations in RPGR, retinitis pigmentosa GTPase regulator, are associated with RP3 type of Xlinked retinitis pigmentosa, a severe, non-syndromic form of retinal degeneration. In the majority of subjects RPGR mutations are associated with a typical rod-cone degeneration, but in a small number, cone-rod dystrophy, deafness, and abnormalities in respiratory cilia have been noted. Alternative splicing of RPGR is complex in all species examined. In RP3 patients, mutations have been found in exons 1 14 and ORF15, thus delineating a transcript necessary for normal retinal function in humans. The great majority of mutations are predicted to result in premature termination of translation. These mutations are scattered over exons 1 14 and ORF15, while most missense mutations occur in a domain with homology to the protein RCC1, encoded by exons 1 10. Exon ORF15 is a hot spot for mutation, at least in the British population, in which it harbors 80% of the mutations found within a sample of 47 X-linked retinitis pigmentosa patients. Most RPGR mutations are unique to single families, which makes it difficult to demonstrate phenotype genotype correlations. Hum Mutat 19:486 500, 2002.

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Section: Retina-specific Phenotypementioning

confidence: 90%

Section: Mutations and Alternative Splicingmentioning

confidence: 99%

Section: Foundmentioning

confidence: 99%

Section: Mutation Screening Of Exon Orf15mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutations ofRPGR in X-linked retinitis pigmentosa (RP3)

Vervoort

Wright

2002

Hum. Mutat.

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Genomewide Homozygosity Mapping and Molecular Analysis of a Candidate Gene Located on 22q13 (Fibulin-1) in a Previously Undescribed Vitreoretinal Dystrophy

Weigell‐Weber¹

2003

Arch Ophthalmol

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Objectives:To localize the gene that causes an autosomal recessively inherited vitreoretinal dystrophy that has not been described, to our knowledge, and to analyze a candidate gene mapped to 22q13 (fibulin-1 [FBLN1]).Methods: Homozygosity mapping with 500 microsatellite markers spread over the whole genome (mean distance, 7.2 centimorgans [cM]) and mutation analysis of the complete coding region of FBLN1.Results: Homozygosity for all analyzed markers was found in the 4 affected siblings in a region on chromosome 22 encompassing 12 cM from D22S444 (centro-meric) to D22S1170 (telomeric). Lod scores were between 0.017 and 2.36 (theta=0). A mutation analysis of the complete coding region of FBLN1, which encodes interacting extracellular matrix proteins, revealed 4 previously undescribed single nucleotide polymorphisms.Conclusions: A genomewide homozygosity mapping analysis supported the hypothesis that the gene responsible for a unique vitreoretinal dystrophy is located on chromosome 22q13. No obviously pathogenic mutation was found in the candidate gene, FBLN1.

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Identification of a Novel RPGR Exon ORF15 Mutation in a Family With X-linked Retinitis Pigmentosa

Jin

Gu²,

Ma³

et al. 2007

Arch Ophthalmol

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To investigate the phenotypic and genotypic characteristics of a novel mutation associated with X-linked retinitis pigmentosa (XLRP). Methods: Six individuals in a family with XLRP were recruited, and clinical examinations were performed. All of the members were genotyped with microsatellite markers at loci that were considered to be associated with XLRP. The retinitis pigmentosa GTPase regulator gene (RPGR) was comprehensively screened using direct polymerase chain reaction sequencing. Results: Genotyping analysis showed that the affected individuals in the family shared a common haplotype with selected markers. The patients demonstrated severe retinal degenerative phenotypes consistent with XLRP. Mu-tational screening of RPGR demonstrated a novel mutation, g.ORF15ϩ1232_1233delGG. Conclusions: We identified a novel mutation in the 3Ј end of a highly repetitive region of exon open reading frame 15 (ORF15) and documented the detailed phenotypes of the patients with XLRP with the mutation. The clinical phenotype was consistent with XLRP, supporting the observation that the mutations in the 3Ј end of the ORF15 coding sequence give rise to XLRP. Clinical Relevance: The mutation in the 3Ј end of the ORF15 coding sequence can lead to a spectrum of phenotypes, and the cone-predominant phenotype-related mutations can be located irregularly in exon ORF15.

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Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa

Cited by 374 publications

References 20 publications

Mutations ofRPGR in X-linked retinitis pigmentosa (RP3)

Mutations ofRPGR in X-linked retinitis pigmentosa (RP3)

Genomewide Homozygosity Mapping and Molecular Analysis of a Candidate Gene Located on 22q13 (Fibulin-1) in a Previously Undescribed Vitreoretinal Dystrophy

Identification of a Novel RPGR Exon ORF15 Mutation in a Family With X-linked Retinitis Pigmentosa

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