#600852
Table of Contents
Cytogenetic location: 17q23.2 Genomic coordinates (GRCh38): 17:60,200,001-63,100,000
A number sign (#) is used with this entry because of evidence that retinitis pigmentosa-17 (RP17) is caused by duplication or triplication in the chromosome 17q22-q23 region that results in disruption of topologically associated domains (TADs) and increased retinal expression of GDPD1 (616317).
For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Retinitis pigmentosa-17 (RP17) is characterized by relatively mild disease, with decreased visual acuity, visual field constriction, nyctalopia, and slow progression. Many affected individuals have preserved central vision and acuity until the sixth or seventh decades of life (de Bruijn et al., 2020).
For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Den Hollander et al. (1999) studied a large 3-generation Dutch family with retinitis pigmentosa. Expression of the disease was variable, with visual acuity ranging from 20/20 to 20/200, and peripheral visual fields from a pericentral scotoma to a tubular remnant of 10 degrees, in the third decade of life. Appearance of the fundus ranged from a granular retinal pigment epithelium to pigment dispersion, narrowed arterioles, and atrophic patches. The electrooculogram varied from slightly subnormal to flat. Electroretinography responses were low-normal, showing diminished rod activity or a strongly diminished cone and rod function without predominance of either.
Bardien et al. (1995) and Bardien et al. (1997) reported 2 unrelated South African families with autosomal dominant retinitis pigmentosa mapping to chromosome 17q22. Yang et al. (2005) reported 13 affected individuals in a large Caucasian family (family A) that was found to be an offshoot of the family reported by Bardien et al. (1995). Reduction in night and peripheral vision manifested at around age 15, followed by rod photoreceptor atrophy, bone spicule pigmentation, and concomitant cone photoreceptor dysfunction manifested by photophobia, color vision changes, and decreased central vision. ERG demonstrated reduction of both rod and cone responses.
The transmission pattern of RP17 in families studied by de Bruijn et al. (2020) was consistent with autosomal dominant inheritance.
Bardien et al. (1995) identified a form of autosomal dominant retinitis pigmentosa through linkage analysis with microsatellite markers in a large South African kindred. After exclusion of 13 RP candidate gene loci, including rhodopsin (RHO; 180380) and peripherin/RDS (PRPH2; 179605), they obtained positive lod scores at zero recombination for D17S808 (maximum lod = 4.63) and D17S807 (maximum lod = 5.69). Multipoint analysis gave a maximum lod score of 8.28 between these 2 markers. From haplotype analysis, the disease locus was found to lie in the interval between markers D17S809 and D17S942. Bardien et al. (1995) stated that the immigrant progenitor of the South African family in which they demonstrated linkage had numerous children and they studied only a single branch of the kindred. Further children of the initial immigrant also inherited the RP gene. Due to a founder effect, this mutation could be a common cause of autosomal dominant RP in South Africans of European descent.
Bardien et al. (1997) used a new series of microsatellite markers to localize the disease locus to 17q22. In addition, a second South African autosomal dominant RP family was shown to be linked to 17q22. Disease-associated haplotypes constructed for both families and multipoint linkage analysis placed the gene in a 10-cM interval between D17S1607 and D17S1874. Two candidate genes on 17q were excluded by finding recombination events between these genes and RP17: PDEG and TIMP2. Bardien-Kruger et al. (1999) studied an additional 17 members from the 2 unrelated South African families and refined the locus to a 1-cM interval between D17S1604 and D17S948.
In a large Dutch family with autosomal dominant RP, den Hollander et al. (1999) demonstrated linkage to the RP17 locus on 17q22 and refined the RP17 critical region to a 7.7-cM interval between markers D17S1607 and D17S948. Two positional candidate genes, AOC2 (602268) and GNGT2 (139391), were excluded by mutation analysis.
Using SNP haplotyping in an extended pedigree (NL1) of the large Dutch family with RP mapping to chromosome 17q22, originally reported by den Hollander et al. (1999), de Bruijn et al. (2020) refined the locus to a 5.16-Mb interval. In parallel, de Bruijn et al. (2020) performed whole-exome sequencing (WES) and whole-genome sequencing (WGS) in a large 9-generation British family (UK1) segregating autosomal dominant RP, and identified a disease-associated haplotype on chromosome 17. By interrogation of unsolved inherited retinal disease sequence data in UK databases, they identified 11 additional UK autosomal dominant RP families with the same haplotype, establishing it as a founder haplotype and refining it to a 4.4-Mb interval on chromosome 17q22. The authors noted that this genomic interval overlapped the RP17 locus previously described in families of Dutch and South African origin; however, no rare coding, intronic, or upstream variants in the CA4 gene were identified in the Dutch or UK families.
In an extended Dutch pedigree with autosomal dominant RP (NL1), originally reported by den Hollander et al. (1999), de Bruijn et al. (2020) analyzed genome and exome data for copy number variants and structural variants (SVs) and identified a 226-kb duplication within the RP17 locus (chr17:57,291,905_57,518,137dup; GRCh37), which they designated 'NL-SV1.' The SV segregated fully with the adRP phenotype in the family, and no overlapping SVs were found in exomes of approximately 7,500 controls. In 12 UK families with adRP mapping to the RP17 locus and exhibiting a founder haplotype, WGS revealed a duplicated inversion on chromosome 17 (chr17:57,456,098-57,468,960delins57,275,839_57,559,114inv; GRCh37), which the authors designated 'UK-SV2.' UK-SV2 segregated fully with disease in all families for which DNA was available, and was not found in WGS data from 58,000 UK controls. WGS in 2 South African families with RP linked to the RP17 locus, previously reported by Bardien et al. (1995) (family SA1) and Bardien et al. (1997) (family SA2), revealed an identical SV (SA-SV3) in both families, and a founder effect was confirmed when SA-SV3 was identified in 2 additional families of South African origin (SA3 and SA4). In a Canadian family with adRP, a different inversion/duplication event (CA-SV4) was identified at 17q22. Further analysis of WGS and WES data for genetically unexplained adRP-affected families revealed 4 additional unique complex SVs in 4 unrelated families of Dutch or UK origin (NL-SV5, UK-SV6, UK-SV7, and UK-SV8). All of the RP17 SVs shared an 11.5-kb common duplicated or triplicated region (chr17:57,499,214-57,510,765; GRCh37), with unique breakpoints disrupting the genomic region extending from the YPEL2 gene (609723) to the long noncoding RNA LINC01476. Analysis of breakpoint junction sequences demonstrated the presence of repetitive elements, suggesting that potential mechanisms for the SVs include a combination of microhomology-mediated repair and nonhomologous end-joining events. The SVs segregated with disease and were fully penetrant in all families for which DNA was available; none were found in gnomAD or the Database of Genomic Variants. Functional analysis using patient fibroblasts demonstrated altered topologically-associating domain (TAD) structures that create ectopic contacts between GDPD1 (616317) and YPEL2-associated retinal enhancers. The authors concluded that altered TAD structures resulting in increased retinal expression of GDPD1, which they confirmed by qPCR, is the likely convergent mechanism of disease, consistent with a dominant gain of function.
In affected members from 12 UK families with autosomal dominant RP associated with the UK-SV2 duplicated inversion, de Bruijn et al. (2020) noted that foveal sparing and cystoid macular edema were common findings. They also observed that in a UK family with a triplicated SV (UK-SV6), the 2 affected individuals for whom clinical information was available showed an earlier age of onset and more severe phenotype.
In affected members of the 2 South African families with RP17 reported by Bardien et al., 1995 and Bardien et al., 1997, Rebello et al. (2004) had identified an R14W mutation in the CA4 gene (114760.0001); however, based on the report of de Bruijn et al. (2020) and the 4% population frequency of this variant identified in healthy controls in northern Sweden (Golovleva et al., 2010; de Bruijn et al., 2020), the variant has been reclassified as a variant of unknown significance.
Bardien, S., Ebenezer, N., Greenberg, J., Inglehearn, C. F., Bartmann, L., Goliath, R., Beighton, P., Ramesar, R., Bhattacharya, S. S. An eighth locus for autosomal dominant retinitis pigmentosa is linked to chromosome 17q. Hum. Molec. Genet. 4: 1459-1462, 1995. [PubMed: 7581389, related citations] [Full Text]
Bardien, S., Ramesar, R., Bhattacharya, S., Greenberg, J. Retinitis pigmentosa locus on 17q (RP17): fine localization to 17q22 and exclusion of the PDEG and TIMP2 genes. Hum. Genet. 101: 13-17, 1997. [PubMed: 9385361, related citations] [Full Text]
Bardien-Kruger, S., Greenberg, J., Tubb, B., Bryan, J., Queimado, L., Lovett, M., Ramesar, R. S. Refinement of the RP17 locus for autosomal dominant retinitis pigmentosa, construction of a YAC contig and investigation of the candidate gene retinal fascin. Europ. J. Hum. Genet. 7: 332-338, 1999. [PubMed: 10234509, related citations] [Full Text]
de Bruijn, S. E., Fiorentino, A., Ottaviani, D., Fanucchi, S., Melo, U. S., Corral-Serrano, J. C., Mulders, T., Georgiou, M., Rivolta, C., Pontikos, N., Arno, G., Roberts, L., and 25 others. Structural variants create new topological-associated domains and ectopic retinal enhancer-gene contact in dominant retinitis pigmentosa. Am. J. Hum. Genet. 107: 802-814, 2020. [PubMed: 33022222, images, related citations] [Full Text]
den Hollander, A. I., van der Velde-Visser, S. D., Pinckers, A. J. L. G., Hoyng, C. B., Brunner, H. G., Cremers, F. P. M. Refined mapping of the gene for autosomal dominant retinitis pigmentosa (RP17) on chromosome 17q22. Hum. Genet. 104: 73-76, 1999. [PubMed: 10071195, related citations] [Full Text]
Golovleva, I., Kohn, L., Burstedt, M., Daiger, S., Sandgren, O. Mutation spectra in autosomal dominant and recessive retinitis pigmentosa in northern Sweden. Adv. Exp. Med. Biol. 664: 255-262, 2010. [PubMed: 20238024, images, related citations] [Full Text]
Rebello, G., Ramesar, R., Vorster, A., Roberts, L., Ehrenreich, L., Oppon, E., Gama, D., Bardien, S., Greenberg, J., Bonapace, G., Waheed, A., Shah, G. N., Sly, W. S. Apoptosis-inducing signal sequence mutation in carbonic anhydrase IV identified in patients with the RP17 form of retinitis pigmentosa. Proc. Nat. Acad. Sci. 101: 6617-6622, 2004. [PubMed: 15090652, images, related citations] [Full Text]
Yang, Z., Alvarez, B. V., Chakarova, C., Jiang, L., Karan, G., Frederick, J. M., Zhao, Y., Sauve, Y., Li, X., Zrenner, E., Wissinger, B., Den Hollander, A. I., Katz, B., Baehr, W., Cremers, F. P., Casey, J. R., Bhattacharya, S. S., Zhang, K. Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal photoreceptor degeneration. Hum. Molec. Genet. 14: 255-265, 2005. [PubMed: 15563508, related citations] [Full Text]
ORPHA: 791; DO: 0110404;
Cytogenetic location: 17q23.2 Genomic coordinates (GRCh38): 17:60,200,001-63,100,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q23.2 | Retinitis pigmentosa 17 | 600852 | Autosomal dominant | 4 |
A number sign (#) is used with this entry because of evidence that retinitis pigmentosa-17 (RP17) is caused by duplication or triplication in the chromosome 17q22-q23 region that results in disruption of topologically associated domains (TADs) and increased retinal expression of GDPD1 (616317).
For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Retinitis pigmentosa-17 (RP17) is characterized by relatively mild disease, with decreased visual acuity, visual field constriction, nyctalopia, and slow progression. Many affected individuals have preserved central vision and acuity until the sixth or seventh decades of life (de Bruijn et al., 2020).
For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Den Hollander et al. (1999) studied a large 3-generation Dutch family with retinitis pigmentosa. Expression of the disease was variable, with visual acuity ranging from 20/20 to 20/200, and peripheral visual fields from a pericentral scotoma to a tubular remnant of 10 degrees, in the third decade of life. Appearance of the fundus ranged from a granular retinal pigment epithelium to pigment dispersion, narrowed arterioles, and atrophic patches. The electrooculogram varied from slightly subnormal to flat. Electroretinography responses were low-normal, showing diminished rod activity or a strongly diminished cone and rod function without predominance of either.
Bardien et al. (1995) and Bardien et al. (1997) reported 2 unrelated South African families with autosomal dominant retinitis pigmentosa mapping to chromosome 17q22. Yang et al. (2005) reported 13 affected individuals in a large Caucasian family (family A) that was found to be an offshoot of the family reported by Bardien et al. (1995). Reduction in night and peripheral vision manifested at around age 15, followed by rod photoreceptor atrophy, bone spicule pigmentation, and concomitant cone photoreceptor dysfunction manifested by photophobia, color vision changes, and decreased central vision. ERG demonstrated reduction of both rod and cone responses.
The transmission pattern of RP17 in families studied by de Bruijn et al. (2020) was consistent with autosomal dominant inheritance.
Bardien et al. (1995) identified a form of autosomal dominant retinitis pigmentosa through linkage analysis with microsatellite markers in a large South African kindred. After exclusion of 13 RP candidate gene loci, including rhodopsin (RHO; 180380) and peripherin/RDS (PRPH2; 179605), they obtained positive lod scores at zero recombination for D17S808 (maximum lod = 4.63) and D17S807 (maximum lod = 5.69). Multipoint analysis gave a maximum lod score of 8.28 between these 2 markers. From haplotype analysis, the disease locus was found to lie in the interval between markers D17S809 and D17S942. Bardien et al. (1995) stated that the immigrant progenitor of the South African family in which they demonstrated linkage had numerous children and they studied only a single branch of the kindred. Further children of the initial immigrant also inherited the RP gene. Due to a founder effect, this mutation could be a common cause of autosomal dominant RP in South Africans of European descent.
Bardien et al. (1997) used a new series of microsatellite markers to localize the disease locus to 17q22. In addition, a second South African autosomal dominant RP family was shown to be linked to 17q22. Disease-associated haplotypes constructed for both families and multipoint linkage analysis placed the gene in a 10-cM interval between D17S1607 and D17S1874. Two candidate genes on 17q were excluded by finding recombination events between these genes and RP17: PDEG and TIMP2. Bardien-Kruger et al. (1999) studied an additional 17 members from the 2 unrelated South African families and refined the locus to a 1-cM interval between D17S1604 and D17S948.
In a large Dutch family with autosomal dominant RP, den Hollander et al. (1999) demonstrated linkage to the RP17 locus on 17q22 and refined the RP17 critical region to a 7.7-cM interval between markers D17S1607 and D17S948. Two positional candidate genes, AOC2 (602268) and GNGT2 (139391), were excluded by mutation analysis.
Using SNP haplotyping in an extended pedigree (NL1) of the large Dutch family with RP mapping to chromosome 17q22, originally reported by den Hollander et al. (1999), de Bruijn et al. (2020) refined the locus to a 5.16-Mb interval. In parallel, de Bruijn et al. (2020) performed whole-exome sequencing (WES) and whole-genome sequencing (WGS) in a large 9-generation British family (UK1) segregating autosomal dominant RP, and identified a disease-associated haplotype on chromosome 17. By interrogation of unsolved inherited retinal disease sequence data in UK databases, they identified 11 additional UK autosomal dominant RP families with the same haplotype, establishing it as a founder haplotype and refining it to a 4.4-Mb interval on chromosome 17q22. The authors noted that this genomic interval overlapped the RP17 locus previously described in families of Dutch and South African origin; however, no rare coding, intronic, or upstream variants in the CA4 gene were identified in the Dutch or UK families.
In an extended Dutch pedigree with autosomal dominant RP (NL1), originally reported by den Hollander et al. (1999), de Bruijn et al. (2020) analyzed genome and exome data for copy number variants and structural variants (SVs) and identified a 226-kb duplication within the RP17 locus (chr17:57,291,905_57,518,137dup; GRCh37), which they designated 'NL-SV1.' The SV segregated fully with the adRP phenotype in the family, and no overlapping SVs were found in exomes of approximately 7,500 controls. In 12 UK families with adRP mapping to the RP17 locus and exhibiting a founder haplotype, WGS revealed a duplicated inversion on chromosome 17 (chr17:57,456,098-57,468,960delins57,275,839_57,559,114inv; GRCh37), which the authors designated 'UK-SV2.' UK-SV2 segregated fully with disease in all families for which DNA was available, and was not found in WGS data from 58,000 UK controls. WGS in 2 South African families with RP linked to the RP17 locus, previously reported by Bardien et al. (1995) (family SA1) and Bardien et al. (1997) (family SA2), revealed an identical SV (SA-SV3) in both families, and a founder effect was confirmed when SA-SV3 was identified in 2 additional families of South African origin (SA3 and SA4). In a Canadian family with adRP, a different inversion/duplication event (CA-SV4) was identified at 17q22. Further analysis of WGS and WES data for genetically unexplained adRP-affected families revealed 4 additional unique complex SVs in 4 unrelated families of Dutch or UK origin (NL-SV5, UK-SV6, UK-SV7, and UK-SV8). All of the RP17 SVs shared an 11.5-kb common duplicated or triplicated region (chr17:57,499,214-57,510,765; GRCh37), with unique breakpoints disrupting the genomic region extending from the YPEL2 gene (609723) to the long noncoding RNA LINC01476. Analysis of breakpoint junction sequences demonstrated the presence of repetitive elements, suggesting that potential mechanisms for the SVs include a combination of microhomology-mediated repair and nonhomologous end-joining events. The SVs segregated with disease and were fully penetrant in all families for which DNA was available; none were found in gnomAD or the Database of Genomic Variants. Functional analysis using patient fibroblasts demonstrated altered topologically-associating domain (TAD) structures that create ectopic contacts between GDPD1 (616317) and YPEL2-associated retinal enhancers. The authors concluded that altered TAD structures resulting in increased retinal expression of GDPD1, which they confirmed by qPCR, is the likely convergent mechanism of disease, consistent with a dominant gain of function.
In affected members from 12 UK families with autosomal dominant RP associated with the UK-SV2 duplicated inversion, de Bruijn et al. (2020) noted that foveal sparing and cystoid macular edema were common findings. They also observed that in a UK family with a triplicated SV (UK-SV6), the 2 affected individuals for whom clinical information was available showed an earlier age of onset and more severe phenotype.
In affected members of the 2 South African families with RP17 reported by Bardien et al., 1995 and Bardien et al., 1997, Rebello et al. (2004) had identified an R14W mutation in the CA4 gene (114760.0001); however, based on the report of de Bruijn et al. (2020) and the 4% population frequency of this variant identified in healthy controls in northern Sweden (Golovleva et al., 2010; de Bruijn et al., 2020), the variant has been reclassified as a variant of unknown significance.
Bardien, S., Ebenezer, N., Greenberg, J., Inglehearn, C. F., Bartmann, L., Goliath, R., Beighton, P., Ramesar, R., Bhattacharya, S. S. An eighth locus for autosomal dominant retinitis pigmentosa is linked to chromosome 17q. Hum. Molec. Genet. 4: 1459-1462, 1995. [PubMed: 7581389] [Full Text: https://doi.org/10.1093/hmg/4.8.1459]
Bardien, S., Ramesar, R., Bhattacharya, S., Greenberg, J. Retinitis pigmentosa locus on 17q (RP17): fine localization to 17q22 and exclusion of the PDEG and TIMP2 genes. Hum. Genet. 101: 13-17, 1997. [PubMed: 9385361] [Full Text: https://doi.org/10.1007/s004390050577]
Bardien-Kruger, S., Greenberg, J., Tubb, B., Bryan, J., Queimado, L., Lovett, M., Ramesar, R. S. Refinement of the RP17 locus for autosomal dominant retinitis pigmentosa, construction of a YAC contig and investigation of the candidate gene retinal fascin. Europ. J. Hum. Genet. 7: 332-338, 1999. [PubMed: 10234509] [Full Text: https://doi.org/10.1038/sj.ejhg.5200302]
de Bruijn, S. E., Fiorentino, A., Ottaviani, D., Fanucchi, S., Melo, U. S., Corral-Serrano, J. C., Mulders, T., Georgiou, M., Rivolta, C., Pontikos, N., Arno, G., Roberts, L., and 25 others. Structural variants create new topological-associated domains and ectopic retinal enhancer-gene contact in dominant retinitis pigmentosa. Am. J. Hum. Genet. 107: 802-814, 2020. [PubMed: 33022222] [Full Text: https://doi.org/10.1016/j.ajhg.2020.09.002]
den Hollander, A. I., van der Velde-Visser, S. D., Pinckers, A. J. L. G., Hoyng, C. B., Brunner, H. G., Cremers, F. P. M. Refined mapping of the gene for autosomal dominant retinitis pigmentosa (RP17) on chromosome 17q22. Hum. Genet. 104: 73-76, 1999. [PubMed: 10071195] [Full Text: https://doi.org/10.1007/s004390050912]
Golovleva, I., Kohn, L., Burstedt, M., Daiger, S., Sandgren, O. Mutation spectra in autosomal dominant and recessive retinitis pigmentosa in northern Sweden. Adv. Exp. Med. Biol. 664: 255-262, 2010. [PubMed: 20238024] [Full Text: https://doi.org/10.1007/978-1-4419-1399-9_29]
Rebello, G., Ramesar, R., Vorster, A., Roberts, L., Ehrenreich, L., Oppon, E., Gama, D., Bardien, S., Greenberg, J., Bonapace, G., Waheed, A., Shah, G. N., Sly, W. S. Apoptosis-inducing signal sequence mutation in carbonic anhydrase IV identified in patients with the RP17 form of retinitis pigmentosa. Proc. Nat. Acad. Sci. 101: 6617-6622, 2004. [PubMed: 15090652] [Full Text: https://doi.org/10.1073/pnas.0401529101]
Yang, Z., Alvarez, B. V., Chakarova, C., Jiang, L., Karan, G., Frederick, J. M., Zhao, Y., Sauve, Y., Li, X., Zrenner, E., Wissinger, B., Den Hollander, A. I., Katz, B., Baehr, W., Cremers, F. P., Casey, J. R., Bhattacharya, S. S., Zhang, K. Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal photoreceptor degeneration. Hum. Molec. Genet. 14: 255-265, 2005. [PubMed: 15563508] [Full Text: https://doi.org/10.1093/hmg/ddi023]
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