Retinitis pigmentosa. The Friedenwald Lecture.

https://www.zora.uzh.ch/id/eprint/33361/3/Berger_et_al_The_molecular_basis_of_human_retinal_and_vitreoretinal_diseases_2010.pdf

The molecular basis of human retinal and vitreoretinal diseases.

X-linked retinitis pigmentosa (xlRP) is a severe progressive retinal degeneration which affects about 1 in 25,000 of the population. The most common form of xlRP, RP3, has been localised to the interval between CYBB and OTC in Xp21.1 by linkage analysis and deletion mapping. Identification of microdeletions within this region has now led to the positional cloning of a gene, RPGR, that spans 60 kg of genomic DNA and is ubiquitously expressed. The predicted 90 kD protein contains in its N-terminal half a tandem repeat structure highly similar to RCC1 (regulator of chromosome condensation), suggesting an interaction with a small GTPase. The C-terminal half contains a domain, rich in acidic residues, and ends in a potential isoprenylation anchorage site. The two intragenic deletions, two nonsense and three missense mutations within conserved domains provide evidence that RPGR (retinitis pigmentosa GTPase regulator) is the RP3 gene.

A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3).

Retinitis pigmentosa (RP) is a group of inherited disorders affecting 1 in 3000-7000 people and characterized by abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium of the retina which lead to progressive visual loss. RP can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. While usually limited to the eye, RP may also occur as part of a syndrome as in the Usher syndrome and Bardet-Biedl syndrome. Over 40 genes have been associated with RP so far, with the majority of them expressed in either the photoreceptors or the retinal pigment epithelium. The tremendous heterogeneity of the disease makes the genetics of RP complicated, thus rendering genotype-phenotype correlations not fully applicable yet. In addition to the multiplicity of mutations, in fact, different mutations in the same gene may cause different diseases. We will here review which genes are involved in the genesis of RP and how mutations can lead to retinal degeneration. In the future, a more thorough analysis of genetic and clinical data together with a better understanding of the genotype-phenotype correlation might allow to reveal important information with respect to the likelihood of disease development and choices of therapy.

/pdf/retinitis-pigmentosa-genes-and-disease-mechanisms-zv0jxzt976.pdf

Retinitis Pigmentosa: Genes and Disease Mechanisms

X-linked retinitis pigmentosa (XLRP) results from mutations in at least two different loci, designated RP2 and RP3, located at Xp11.3 and Xp21.1, respectively. The RP3 gene was recently isolated by positional cloning, whereas the RP2 locus was mapped genetically to a 5-cM interval. We have screened this region for genomic rearrangements by the YAC representation hybridization (YRH) technique and detected a LINE1 (L1) insertion in one XLRP patient. The L1 retrotransposition occurred in an intron of a novel gene that consisted of five exons and encoded a polypeptide of 350 amino acids. Subsequently, nonsense, missense and frameshift mutations, as well as two small deletions, were identified in six additional patients. The predicted gene product shows homology with human cofactor C, a protein involved in the ultimate step of s-tubulin folding. Our data provide evidence that mutations in this gene, designated RP2, are responsible for progressive retinal degeneration.

Positional cloning of the gene for X-linked retinitis pigmentosa 2

Retinitis pigmentosa (RP) is a group of retinal degenerations characterized by progressive visual field loss, night blindness and pigmentary retinopathy1. Its prevalence is in the region of 1–2 in 5,000 of the general population, making it one of the commoner causes of blindness in early and middle life2,3. Although 36–48% of RP patients are isolated cases, the remainder show autosomal dominant, autosomal recessive or X-linked modes of inheritance4,5. The X-linked variety (XLRP) is found in 14–22% of RP families in the UK2,5. In the present study, X chromosome-specific recombinant DNA probes which can detect restriction fragment length polymorphisms have been used to localize the XLRP gene(s) to a subregion of the X chromosome using linkage analysis. One of the probes, L1.28, has been shown to be closely linked to XLRP in five kindreds,, with 95% confidence limits of 0–15 centimorgans (maximum LOD score of 7.89 at a distance of 3 centimorgans). This suggests that the XLRP locus lies on the proximal part of the short arm of the X chromosome. This probe is potentially useful for carrier detection and early diagnosis in about 40% of cases, provided that genetic heterogeneity can be excluded by analysis of further families.

Close genetic linkage between X-linked retinitis pigmentosa and a restriction fragment length polymorphism identified by recombinant DNA probe L1.28

Informative members of more than twenty families with X-linked retinitis pigmentosa have been sampled by venipuncture and DNA extracted from peripheral blood leucocytes and lymphoblastoid cell lines. X chromosome-specific recombinant DNA probes have been isolated from an X chromosomal genomic DNA library obtained by flow-sorting human chromosomes. These, and similar probes obtained from other laboratories, are being used to identify restriction fragment length polymorphisms in retinitis pigmentosa obligate heterozygotes. By analysis of linkage relationships in the offspring of double heterozygotes, it may be possible to localize the gene(s) responsible for this disorder to a particular subregion of the X-chromosome. Such probes are potentially useful for carrier detection and prenatal diagnosis.

M. Jay

Papers

Close genetic linkage between X-linked retinitis pigmentosa and a restriction fragment length polymorphism identified by recombinant DNA probe L1.28

DNA probes in X-linked retinitis pigmentosa.