Retinitis Pigmentosa

Background

Retinitis Pigmentosa (RP) is the name given to a group of eye diseases often characterised by night blindness and the gradual loss of peripheral vision. RP causes visual field loss, and may lead to eventual blindness, by affecting the light sensitive photoreceptors in the retina. Either the rods or cones may be affected leading to central or peripheral vision loss. There are various types of inheritance with autosomal dominant patients having a milder course than autosomal recessive patients. Unfortunately, RP is a progressive disorder by definition.

OUTLINE

Epidemiology

Pathogenesis

Gross Appearance and Clinical Variants

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

INCIDENCE/PREVALENCE USA 1 in 4000

AGE Young adulthood
Mid 30s to 50s.

PATHOGENESIS CHARACTERIZATION

AUTOSOMAL DOMINANT

Mutations in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 in Spanish families with autosomal dominant retinitis pigmentosa.

Martinez-Gimeno M, Gamundi MJ, Hernan I, Maseras M, Milla E, Ayuso C, Garcia-Sandoval B, Beneyto M, Vilela C, Baiget M, Antinolo G, Carballo M.

Laboratory of Biology and Molecular Genetics, Laboratory of Service, Consorci Sanitari de Terrassa, Hospital de Terrassa, Terrassa, Spain.
Invest Ophthalmol Vis Sci. 2003 May;44(5):2171-7 Abstract uqote
PURPOSE: Mutations in the systemically expressed pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 have recently been associated with autosomal dominant retinitis pigmentosa (adRP). This study was intended to identify mutations in PRPF3, PRPF8, and PRPF31 in 150 Spanish families affected by adRP, to measure the contribution of mutations in these genes to adRP in that population, and to correlate RP phenotype expression with mutations in pre-mRNA splicing-factor genes.

METHODS: Denaturing gradient gel electrophoresis (DGGE) and direct genomic sequencing were used to evaluate the complete coding region and flanking intronic sequences of the PRPF31 gene, exon 42 of PRPF8, and exon 11 of PRPF3 for mutations in 150 unrelated index patients with adRP. Ophthalmic and electrophysiological examination of patients with RP and their relatives was performed according to preexisting protocols.

RESULTS: Three nonsense mutations caused by insertion and deletion sequences and two missense mutations (Arg2310Gly) and within the stop codon of the PRPF8 gene (TGA-->TTG), were detected in five unrelated heterozygous patients. Three patients were heterozygous carriers of different nonsense mutations in exon 8 of the PRPF31, gene and one Thr494Met mutation was found in exon 11 of the PRPF3 gene. Cosegregation of the mutation in PRPF8 and PRPF3 with adRP was observed. However, two nonsense mutations in PRPF31 causing adRP detected in two families showed asymptomatic carriers.

CONCLUSIONS: Nine mutations, six of which are novel, in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31, causing adRP have been identified in the Spanish population. Their contribution to adRP is approximately 5% after correction in relation to mutations found in other genes causing adRP. The patients carrying a mutation in the pre-mRNA splicing-factor PRPF8 gene showed a type 1 diffuse RP. The existence of asymptomatic carriers of the nonsense mutation in the PRPF31 gene suggests incomplete penetrance for these mutations in the families.

Disease mechanism for retinitis pigmentosa (RP11) caused by mutations in the splicing factor gene PRPF31.

Deery EC, Vithana EN, Newbold RJ, Gallon VA, Bhattacharya SS, Warren MJ, Hunt DM, Wilkie SE.

School of Biological Sciences, Queen Mary, University of London, London E1 4NS, UK.

Hum Mol Genet. 2002 Dec 1;11(25):3209-19. Abstract quote
This study investigates the functional consequences of two mutations, A194E and A216P, in the splicing factor gene PRPF31 linked to autosomal dominant retinitis pigmentosa (RP11).

Using a yeast complementation assay, we demonstrate that introduction of the human A216P mutation into the yeast orthologue PRP31p results in only partial rescue of growth at the restrictive temperature, indicating that splicing function is not fully restored. An in vivo assay of splicing function in human cells using a bovine rod opsin splicing template did not detect any defect in splicing efficiency or accuracy attributable to either mutation, suggesting that neither has a dominant negative effect on splicing.

However, western analysis and immunofluorescence microscopy of mammalian cells transfected with PRPF31 revealed that both mutations substantially hinder translocation of the protein into the nucleus. The overall effect may thus be an insufficiency in splicing function, which is revealed only under conditions of elevated splicing demand.

With the need to replenish disc proteins on a daily basis, such conditions will exist in rod photoreceptors and this may underlie the disease pathology.

X-LINKED

X-linked retinitis pigmentosa: RPGR mutations in most families with definite X linkage and clustering of mutations in a short sequence stretch of exon ORF15.

Bader I, Brandau O, Achatz H, Apfelstedt-Sylla E, Hergersberg M, Lorenz B, Wissinger B, Wittwer B, Rudolph G, Meindl A, Meitinger T.

Institute of Human Genetics, National Research Center for Environment and Health (GSF), Neuherberg, Germany.
Invest Ophthalmol Vis Sci. 2003 Apr;44(4):1458-63. Abstract quote
PURPOSE: A comprehensive screening was conducted for RP2 and retinitis pigmentosa GTPase regulator (RPGR) gene mutations including RPGR exon ORF15 in 58 index patients. The frequency of RPGR mutations was assessed in families with definite X-linked recessive disease (xlRP), and a strategy for analyzing the highly repetitive mutational hot spot in exon ORF15 is provided.

METHODS: Fifty-eight apparently unrelated index-patients were screened for mutations in all coding exons of the RP2 and the RPGR genes, including splice-sites, by single-strand conformation polymorphism (SSCP) analysis, except for RPGR exon ORF15. A strategy for directly sequencing the large repetitive stretch of exon ORF15 from a 1.6-kb PCR-product was developed. According to pedigree size and evidence for X linkage, families were subdivided into three categories.

RESULTS: Screening of 58 xlRP families revealed RP2 mutations in 8% and RPGR mutations in 71% of families with definite X-linked inheritance. Mutations clustered within a approximately 500-bp stretch in exon ORF15. In-frame sequence alterations in exon ORF15 ranged from the deletion of 36 bp to the insertion of 75 bp.

CONCLUSIONS: Mutations in the RPGR gene are estimated to cause 15% to 20% of all cases of RP, higher than any other single RP locus. This report provides a detailed strategy to analyze the mutational hot spot in RPGR exon ORF15, which cannot be screened by standard procedures. The discrepancy of the proportion of families linked to the RP3 locus and those having RPGR mutations is resolved in a subset of families with definite X linkage.

A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa.

Breuer DK, Yashar BM, Filippova E, Hiriyanna S, Lyons RH, Mears AJ, Asaye B, Acar C, Vervoort R, Wright AF, Musarella MA, Wheeler P, MacDonald I, Iannaccone A, Birch D, Hoffman DR, Fishman GA, Heckenlively JR, Jacobson SG, Sieving PA, Swaroop A.

Department of Human Genetics, W.K. Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105, USA.
Am J Hum Genet. 2002 Jun;70(6):1545-54. Abstract quote
X-linked retinitis pigmentosa (XLRP) is a clinically and genetically heterogeneous degenerative disease of the retina. At least five loci have been mapped for XLRP; of these, RP2 and RP3 account for 10%-20% and 70%-90% of genetically identifiable disease, respectively. However, mutations in the respective genes, RP2 and RPGR, were detected in only 10% and 20% of families with XLRP. Mutations in an alternatively spliced RPGR exon, ORF15, have recently been shown to account for 60% of XLRP in a European cohort of 47 families.

We have performed, in a North American cohort of 234 families with RP, a comprehensive screen of the RP2 and RPGR (including ORF15) genes and their 5' upstream regions. Of these families, 91 (39%) show definitive X-linked inheritance, an additional 88 (38%) reveal a pattern consistent with X-linked disease, and the remaining 55 (23%) are simplex male patients with RP who had an early onset and/or severe disease.

In agreement with the previous studies, we show that mutations in the RP2 gene and in the original 19 RPGR exons are detected in <10% and approximately 20% of XLRP probands, respectively. Our studies have revealed RPGR-ORF15 mutations in an additional 30% of 91 well-documented families with X-linked recessive inheritance and in 22% of the total 234 probands analyzed.

We suggest that mutations in an as-yet-uncharacterized RPGR exon(s), intronic changes, or another gene in the region might be responsible for the disease in the remainder of this North American cohort. We also discuss the implications of our studies for genetic diagnosis, genotype-phenotype correlations, and gene-based therapy.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL
More than 70 different genetic defects have been identified:

X-linked (9%)
Autosomal recessive (16%)
A autosomal dominant (22%)
Primary RP or RP simplex (remainder)

TREATMENT CHARACTERIZATION

GENERAL

DEFLAZACORT

Deflazacort treatment of cystoid macular edema in patients affected by Retinitis Pigmentosa: a pilot study.

Giusti C, Forte R, Vingolo EM.

Institute of Ophthalmology, University La Sapienza, Rome, Italy.
Eur Rev Med Pharmacol Sci. 2002 Jan-Feb;6(1):1-8. Abstract quote
BACKGROUND: To investigate the efficacy of a long-term treatment with Deflazacort (DFZ), a third generation synthetic glucocorticoid, in patients affected by Retinitis Pigmentosa (RP) complicated by Cystoid Macular Edema (CME).

METHODS: A randomized group of 10 RP subjects were selected for this pilot study and treated with DFZ for one year according to a standard protocol. Far and near Best Corrected Visual Acuity (BCVA), fluorescein angiography (Heidelberg Retina Angiograph) and computerized perimetry (Humphrey Visual Field Analyzer) were statistically assessed.

RESULTS: Near visual acuities, fluorescein angiographic findings and perimetric data improved significantly (p < 0.01) while far BCVA varied only slightly (p < 0.05). No ocular or systemic side effects were recorded.

CONCLUSIONS: Further case-control studies, also involving a larger number of patients, are required to confirm these preliminary results. However, the present investigation seem to suggest that DFZ could be effective in reducing fluorescein angiographic findings and improving perimetric data and near visual acuities in RP patients, even though the pathogenesis of CME remains poorly understood.

GENE THERAPY

Gene therapy for retinitis pigmentosa.

Bennett J.

FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, PA 19104-6069, USA.
Curr Opin Mol Ther. 2000 Aug;2(4):420-5. Abstract quote
Retinitis pigmentosa (RP) is a group of retinal degenerative diseases in which there is a slow and progressive loss of photoreceptors. There is no cure for RP and photoreceptor loss leads ultimately to blindness.

There has been tremendous progress in the last decade in delineating the molecular basis of RP. Simultaneously, gene transfer experiments have demonstrated that it is possible to deliver transgenes to the retina in vivo in a stable and efficient fashion with minimal toxicity. Proof-of-principle for gene therapy for RP has been established in a number of different animal models.

While much more progress needs to be made before moving from the laboratory to the clinic, gene therapy now holds much promise for slowing or even preventing blindness due to RP.

SURGERY

Vitreoretinal surgery for cystoid macular edema associated with retinitis pigmentosa.

Garcia-Arumi J, Martinez V, Sararols L, Corcostegui B.

Hospital Vall d'Hebron, Universidad Autonoma de Barcelona, Spain.
Ophthalmology. 2003 Jun;110(6):1164-9. Abstract quote
PURPOSE: To evaluate the anatomic and functional outcome of vitreoretinal surgery in eyes with retinitis pigmentosa (RP) and macular edema.

DESIGN: Prospective noncomparative case series.

PARTICIPANTS: Twelve consecutive eyes of eight patients with RP and a documented decrease in visual acuity (VA) to 20/60 or worse caused by macular edema refractory to medical therapy.

METHODS: Pars plana vitrectomy was performed in the 12 eyes, followed by posterior hyaloid dissection, removal of the posterior inner limiting membrane after staining with indocyanine green, and gas tamponade. Preoperative best-corrected VAs ranged from 20/60 to 20/400 (mean, 20/115).

MAIN OUTCOME MEASURES: Changes in VA and foveal thickness as determined by optical coherence tomography (OCT).

RESULTS: The mean preoperative retinal thickness at the fovea was 477 micro m. Optical coherence tomography showed a decrease in macular thickness of >40% in 10 eyes (83.3%), with a mean postoperative foveal thickness of 260 micro m. The mean VA increased from 20/115 to 20/45, with an average of three lines of improvement.

CONCLUSIONS: Our results suggest that vitreoretinal surgery may effectively manage macular edema in RP.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

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Internet Links

Last Updated 7/15/2003

PATHOGENESIS	CHARACTERIZATION
AUTOSOMAL DOMINANT
Mutations in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 in Spanish families with autosomal dominant retinitis pigmentosa. Martinez-Gimeno M, Gamundi MJ, Hernan I, Maseras M, Milla E, Ayuso C, Garcia-Sandoval B, Beneyto M, Vilela C, Baiget M, Antinolo G, Carballo M. Laboratory of Biology and Molecular Genetics, Laboratory of Service, Consorci Sanitari de Terrassa, Hospital de Terrassa, Terrassa, Spain.	Invest Ophthalmol Vis Sci. 2003 May;44(5):2171-7 Abstract uqote PURPOSE: Mutations in the systemically expressed pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 have recently been associated with autosomal dominant retinitis pigmentosa (adRP). This study was intended to identify mutations in PRPF3, PRPF8, and PRPF31 in 150 Spanish families affected by adRP, to measure the contribution of mutations in these genes to adRP in that population, and to correlate RP phenotype expression with mutations in pre-mRNA splicing-factor genes. METHODS: Denaturing gradient gel electrophoresis (DGGE) and direct genomic sequencing were used to evaluate the complete coding region and flanking intronic sequences of the PRPF31 gene, exon 42 of PRPF8, and exon 11 of PRPF3 for mutations in 150 unrelated index patients with adRP. Ophthalmic and electrophysiological examination of patients with RP and their relatives was performed according to preexisting protocols. RESULTS: Three nonsense mutations caused by insertion and deletion sequences and two missense mutations (Arg2310Gly) and within the stop codon of the PRPF8 gene (TGA-->TTG), were detected in five unrelated heterozygous patients. Three patients were heterozygous carriers of different nonsense mutations in exon 8 of the PRPF31, gene and one Thr494Met mutation was found in exon 11 of the PRPF3 gene. Cosegregation of the mutation in PRPF8 and PRPF3 with adRP was observed. However, two nonsense mutations in PRPF31 causing adRP detected in two families showed asymptomatic carriers. CONCLUSIONS: Nine mutations, six of which are novel, in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31, causing adRP have been identified in the Spanish population. Their contribution to adRP is approximately 5% after correction in relation to mutations found in other genes causing adRP. The patients carrying a mutation in the pre-mRNA splicing-factor PRPF8 gene showed a type 1 diffuse RP. The existence of asymptomatic carriers of the nonsense mutation in the PRPF31 gene suggests incomplete penetrance for these mutations in the families.
Disease mechanism for retinitis pigmentosa (RP11) caused by mutations in the splicing factor gene PRPF31. Deery EC, Vithana EN, Newbold RJ, Gallon VA, Bhattacharya SS, Warren MJ, Hunt DM, Wilkie SE. School of Biological Sciences, Queen Mary, University of London, London E1 4NS, UK.	Hum Mol Genet. 2002 Dec 1;11(25):3209-19. Abstract quote This study investigates the functional consequences of two mutations, A194E and A216P, in the splicing factor gene PRPF31 linked to autosomal dominant retinitis pigmentosa (RP11). Using a yeast complementation assay, we demonstrate that introduction of the human A216P mutation into the yeast orthologue PRP31p results in only partial rescue of growth at the restrictive temperature, indicating that splicing function is not fully restored. An in vivo assay of splicing function in human cells using a bovine rod opsin splicing template did not detect any defect in splicing efficiency or accuracy attributable to either mutation, suggesting that neither has a dominant negative effect on splicing. However, western analysis and immunofluorescence microscopy of mammalian cells transfected with PRPF31 revealed that both mutations substantially hinder translocation of the protein into the nucleus. The overall effect may thus be an insufficiency in splicing function, which is revealed only under conditions of elevated splicing demand. With the need to replenish disc proteins on a daily basis, such conditions will exist in rod photoreceptors and this may underlie the disease pathology.
X-LINKED
X-linked retinitis pigmentosa: RPGR mutations in most families with definite X linkage and clustering of mutations in a short sequence stretch of exon ORF15. Bader I, Brandau O, Achatz H, Apfelstedt-Sylla E, Hergersberg M, Lorenz B, Wissinger B, Wittwer B, Rudolph G, Meindl A, Meitinger T. Institute of Human Genetics, National Research Center for Environment and Health (GSF), Neuherberg, Germany.	Invest Ophthalmol Vis Sci. 2003 Apr;44(4):1458-63. Abstract quote PURPOSE: A comprehensive screening was conducted for RP2 and retinitis pigmentosa GTPase regulator (RPGR) gene mutations including RPGR exon ORF15 in 58 index patients. The frequency of RPGR mutations was assessed in families with definite X-linked recessive disease (xlRP), and a strategy for analyzing the highly repetitive mutational hot spot in exon ORF15 is provided. METHODS: Fifty-eight apparently unrelated index-patients were screened for mutations in all coding exons of the RP2 and the RPGR genes, including splice-sites, by single-strand conformation polymorphism (SSCP) analysis, except for RPGR exon ORF15. A strategy for directly sequencing the large repetitive stretch of exon ORF15 from a 1.6-kb PCR-product was developed. According to pedigree size and evidence for X linkage, families were subdivided into three categories. RESULTS: Screening of 58 xlRP families revealed RP2 mutations in 8% and RPGR mutations in 71% of families with definite X-linked inheritance. Mutations clustered within a approximately 500-bp stretch in exon ORF15. In-frame sequence alterations in exon ORF15 ranged from the deletion of 36 bp to the insertion of 75 bp. CONCLUSIONS: Mutations in the RPGR gene are estimated to cause 15% to 20% of all cases of RP, higher than any other single RP locus. This report provides a detailed strategy to analyze the mutational hot spot in RPGR exon ORF15, which cannot be screened by standard procedures. The discrepancy of the proportion of families linked to the RP3 locus and those having RPGR mutations is resolved in a subset of families with definite X linkage.
A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa. Breuer DK, Yashar BM, Filippova E, Hiriyanna S, Lyons RH, Mears AJ, Asaye B, Acar C, Vervoort R, Wright AF, Musarella MA, Wheeler P, MacDonald I, Iannaccone A, Birch D, Hoffman DR, Fishman GA, Heckenlively JR, Jacobson SG, Sieving PA, Swaroop A. Department of Human Genetics, W.K. Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105, USA.	Am J Hum Genet. 2002 Jun;70(6):1545-54. Abstract quote X-linked retinitis pigmentosa (XLRP) is a clinically and genetically heterogeneous degenerative disease of the retina. At least five loci have been mapped for XLRP; of these, RP2 and RP3 account for 10%-20% and 70%-90% of genetically identifiable disease, respectively. However, mutations in the respective genes, RP2 and RPGR, were detected in only 10% and 20% of families with XLRP. Mutations in an alternatively spliced RPGR exon, ORF15, have recently been shown to account for 60% of XLRP in a European cohort of 47 families. We have performed, in a North American cohort of 234 families with RP, a comprehensive screen of the RP2 and RPGR (including ORF15) genes and their 5' upstream regions. Of these families, 91 (39%) show definitive X-linked inheritance, an additional 88 (38%) reveal a pattern consistent with X-linked disease, and the remaining 55 (23%) are simplex male patients with RP who had an early onset and/or severe disease. In agreement with the previous studies, we show that mutations in the RP2 gene and in the original 19 RPGR exons are detected in <10% and approximately 20% of XLRP probands, respectively. Our studies have revealed RPGR-ORF15 mutations in an additional 30% of 91 well-documented families with X-linked recessive inheritance and in 22% of the total 234 probands analyzed. We suggest that mutations in an as-yet-uncharacterized RPGR exon(s), intronic changes, or another gene in the region might be responsible for the disease in the remainder of this North American cohort. We also discuss the implications of our studies for genetic diagnosis, genotype-phenotype correlations, and gene-based therapy.

Epidemiology
Pathogenesis
Gross Appearance and Clinical Variants
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
INCIDENCE/PREVALENCE	USA 1 in 4000
AGE	Young adulthood Mid 30s to 50s.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL	More than 70 different genetic defects have been identified: X-linked (9%) Autosomal recessive (16%) A autosomal dominant (22%) Primary RP or RP simplex (remainder)