Skip to main content

Advertisement

SpringerLink
Log in

Severe autosomal recessive retinitis pigmentosa maps to chromosome 1p13.3–p21.2 between D1S2896 and D1S457 but outside ABCA4

Human Genetics Aims and scope Submit manuscript

Abstract

A severe form of autosomal recessive retinitis pigmentosa (arRP) was identified in a large Pakistani family ascertained in the Punjab province of Pakistan. All affected individuals in the family had night blindness in early childhood, early complete loss of useful vision, and typical RP fundus changes plus macular degeneration. After exclusion of known arRP loci, a genome-wide scan was performed using microsatellite markers at about 10 cM intervals and calculating two-point lod scores. PCR cycle dideoxynucleotide sequencing was used to sequence candidate genes inside the linked region for mutations. RP in this family shows linkage to markers in a 10.5 cM (8.9 Mbp) region of chromosome 1p13.3–p21.2 between D1S2896 and D1S457. D1S485 yields the highest lod score of 6.54 at θ=0. Sequencing the exons and intron–exon boundaries of five candidate genes and six ESTs in this region, OLFM3, GNAI3, LOC126987, FLJ25070, DKFZp586G0123, AV729694, BU662869, BU656110, BU171991, BQ953690, and CA397743, did not identify any causative mutations. This novel locus lies approximately 4.9 cM (7.1 Mbp) from ABCA4, which is excluded from the linked region. Identification and study of this gene may help to elucidate the phenotypic diversity of arRP mapping to this region.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  • Anonymous (1989) Standard for clinical electroretinography. International Standardization Committee. Arch Ophthalmol 107:816–819

  • Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A, Gerrard B, Baird L, Stauffer D, Peiffer A, Rattner A, Smallwood P, Li Y, Anderson KL, Lewis RA, Nathans J, Leppert M, Dean M, Lupski JR (1997) A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 15:236–246

    Article  PubMed  CAS  Google Scholar 

  • Bareil C, Hamel CP, Delague V, Arnaud B, Demaille J, Claustres M (2001) Segregation of a mutation in CNGB1 encoding the beta-subunit of the rod cGMP-gated channel in a family with autosomal recessive retinitis pigmentosa. Hum Genet 108:328–334

    Article  PubMed  CAS  Google Scholar 

  • Boughman JA, Conneally PM, Nance W (1980) Population genetic studies of retinitis pigmentosa. Am J Hum Genet 32:223–225

    PubMed  CAS  Google Scholar 

  • Briggs CE, Rucinski D, Rosenfeld PJ, Hirose T, Berson EL, Dryja TP (2001) Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration. Invest Ophthalmol Vis Sci 42:2229–2236

    PubMed  CAS  Google Scholar 

  • Buch H, Vinding T, La Cour M, Appleyard M, Jensen GB, Nielsen NV (2004) Prevalence and causes of visual impairment and blindness among 9980 Scandinavian adults: the Copenhagen City Eye Study. Ophthalmology 111:53–61

    Article  PubMed  Google Scholar 

  • Burstedt MS, Forsman-Semb K, Golovleva I, Janunger T, Wachtmeister L, Sandgren O (2001) Ocular phenotype of bothnia dystrophy, an autosomal recessive retinitis pigmentosa associated with an R234W mutation in the RLBP1 gene. Arch Ophthalmol 119:260–267

    PubMed  CAS  Google Scholar 

  • Cremers FP, van de Pol DJ, van Driel M, den Hollander AI, van Haren FJ, Knoers NV, Tijmes N, Bergen AA, Rohrschneider K, Blankenagel A, Pinckers AJ, Deutman AF, Hoyng CB (1998) Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt’s disease gene ABCR. Hum Mol Genet 7:355–362

    Article  PubMed  CAS  Google Scholar 

  • den Hollander AI, ten Brink JB, de Kok YJ, van Soest S, van den Born LI, van Driel MA, van de Pol DJ, Payne AM, Bhattacharya SS, Kellner U, Hoyng CB, Westerveld A, Brunner HG, Bleeker-Wagemakers EM, Deutman AF, Heckenlively JR, Cremers FP, Bergen AA (1999) Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). Nat Genet 23:217–221

    Article  PubMed  CAS  Google Scholar 

  • Dryja TP, Finn JT, Peng YW, McGee TL, Berson EL, Yau KW (1995) Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa. Proc Natl Acad Sci USA 92:10177–10181

    Article  PubMed  CAS  Google Scholar 

  • Evans K, Duvall-Young J, Fitzke FW, Arden GB, Bhattacharya SS, Bird AC (1995) Chromosome 19q cone-rod retinal dystrophy. Ocular phenotype. Arch Ophthalmol 113:195–201

    PubMed  CAS  Google Scholar 

  • Finckh U, Xu S, Kumaramanickavel G, Schurmann M, Mukkadan JK, Fernandez ST, John S, Weber JL, Denton MJ, Gal A (1998) Homozygosity mapping of autosomal recessive retinitis pigmentosa locus (RP22) on chromosome 16p12.1-p12.3. Genomics 48:341–345

    Article  PubMed  CAS  Google Scholar 

  • Fukui T, Yamamoto S, Nakano K, Tsujikawa M, Morimura H, Nishida K, Ohguro N, Fujikado T, Irifune M, Kuniyoshi K, Okada AA, Hirakata A, Miyake Y, Tano Y (2002) ABCA4 gene mutations in Japanese patients with Stargardt disease and retinitis pigmentosa. Invest Ophthalmol Vis Sci 43:2819–2824

    PubMed  Google Scholar 

  • Gal A, Li Y, Thompson DA, Weir J, Orth U, Jacobson SG, Apfelstedt-Sylla E, Vollrath D (2000) Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat Genet 26:270–271

    Article  PubMed  CAS  Google Scholar 

  • Gerber S, Rozet JM, van de Pol TJ, Hoyng CB, Munnich A, Blankenagel A, Kaplan J, Cremers FP (1998) Complete exon-intron structure of the retina-specific ATP binding transporter gene (ABCR) allows the identification of novel mutations underlying Stargardt disease. Genomics 48:139–142

    Article  PubMed  CAS  Google Scholar 

  • Gerber S, Rozet JM, Takezawa SI, dos Santos LC, Lopes L, Gribouval O, Penet C, Perrault I, Ducroq D, Souied E, Jeanpierre M, Romana S, Frezal J, Ferraz F, Yu-Umesono R, Munnich A, Kaplan J (2000) The photoreceptor cell-specific nuclear receptor gene (PNR) accounts for retinitis pigmentosa in the Crypto-Jews from Portugal (Marranos), survivors from the Spanish Inquisition. Hum Genet 107:276–284

    Article  PubMed  CAS  Google Scholar 

  • Gregory-Evans K, Kelsell RE, Gregory-Evans CY, Downes SM, Fitzke FW, Holder GE, Simunovic M, Mollon JD, Taylor R, Hunt DM, Bird AC, Moore AT (2000) Autosomal dominant cone-rod retinal dystrophy (CORD6) from heterozygous mutation of GUCY2D, which encodes retinal guanylate cyclase. Ophthalmology 107:55–61

    Article  PubMed  CAS  Google Scholar 

  • Gu S, Kumaramanickavel G, Srikumari CR, Denton MJ, Gal A (1999) Autosomal recessive retinitis pigmentosa locus RP28 maps between D2S1337 and D2S286 on chromosome 2p11-p15 in an Indian family. J Med Genet 36:705–707

    PubMed  CAS  Google Scholar 

  • Hagstrom SA, North MA, Nishina PL, Berson EL, Dryja TP (1998) Recessive mutations in the gene encoding the tubby-like protein TULP1 in patients with retinitis pigmentosa. Nat Genet 18:174–176

    Article  PubMed  CAS  Google Scholar 

  • Hameed A, Khaliq S, Ismail M, Anwar K, Mehdi SQ, Bessant D, Payne AM, Bhattacharya SS (2001) A new locus for autosomal recessive RP (RP29) mapping to chromosome 4q32-q34 in a Pakistani family. Invest Ophthalmol Vis Sci 42:1436–1438

    PubMed  CAS  Google Scholar 

  • Heckenlively JR, Yoser SL, Friedman LH, Oversier JJ (1988) Clinical findings and common symptoms in retinitis pigmentosa. Am J Ophthalmol 105:504–511

    PubMed  CAS  Google Scholar 

  • Huang SH, Pittler SJ, Huang X, Oliveira L, Berson EL, Dryja TP (1995) Autosomal recessive retinitis pigmentosa caused by mutations in the alpha subunit of rod cGMP phosphodiesterase. Nat Genet 11:468–471

    Article  PubMed  CAS  Google Scholar 

  • Jaakson K, Zernant J, Kulm M, Hutchinson A, Tonisson N, Glavac D, Ravnik-Glavac M, Hawlina M, Meltzer MR, Caruso RC, Testa F, Maugeri A, Hoyng CB, Gouras P, Simonelli F, Lewis RA, Lupski JR, Cremers FP, Allikmets R (2003) Genotyping microarray (gene chip) for the ABCR (ABCA4) gene. Hum Mutat 22:395–403

    Article  PubMed  CAS  Google Scholar 

  • Khaliq S, Hameed A, Ismail M, Anwar K, Leroy BP, Mehdi SQ, Payne AM, Bhattacharya SS (2000) Novel locus for autosomal recessive cone-rod dystrophy CORD8 mapping to chromosome 1q12-Q24. Invest Ophthalmol Vis Sci 41:3709–3712

    PubMed  CAS  Google Scholar 

  • Klevering BJ, van Driel M, van de Pol DJ, Pinckers AJ, Cremers FP, Hoyng CB (1999) Phenotypic variations in a family with retinal dystrophy as result of different mutations in the ABCR gene. Br J Ophthalmol 83:914–918

    Article  PubMed  CAS  Google Scholar 

  • Klevering BJ, Maugeri A, Wagner A, Go SL, Vink C, Cremers FP, Hoyng CB (2004) Three families displaying the combination of Stargardt’s disease with cone-rod dystrophy or retinitis pigmentosa. Ophthalmology 111:546–553

    Article  PubMed  Google Scholar 

  • Kohl S, Baumann B, Rosenberg T, Kellner U, Lorenz B, Vadala M, Jacobson SG, Wissinger B (2002) Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. Am J Hum Genet 71:422–425

    Article  PubMed  CAS  Google Scholar 

  • Lathrop GM, Lalouel JM (1984) Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet 36:460–465

    PubMed  CAS  Google Scholar 

  • Lewis RA, Shroyer NF, Singh N, Allikmets R, Hutchinson A, Li Y, Lupski JR, Leppert M, Dean M (1999) Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. Am J Hum Genet 64:422–434

    Article  PubMed  CAS  Google Scholar 

  • Martinez-Mir A, Bayes M, Vilageliu L, Grinberg D, Ayuso C, del Rio T, Garcia-Sandoval B, Bussaglia E, Baiget M, Gonzalez-Duarte R, Balcells S (1997) A new locus for autosomal recessive retinitis pigmentosa (RP19) maps to 1p13–1p21. Genomics 40:142–146

    Article  PubMed  CAS  Google Scholar 

  • Martinez-Mir A, Paloma E, Allikmets R, Ayuso C, del Rio T, Dean M, Vilageliu L, Gonzalez-Duarte R, Balcells S (1998) Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR. Nat Genet 18:11–12

    Article  PubMed  CAS  Google Scholar 

  • Maugeri A, van Driel MA, van de Pol DJ, Klevering BJ, van Haren FJ, Tijmes N, Bergen AA, Rohrschneider K, Blankenagel A, Pinckers AJ, Dahl N, Brunner HG, Deutman AF, Hoyng CB, Cremers FP (1999) The 2588G–>C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease. Am J Hum Genet 64:1024–1035

    Article  PubMed  CAS  Google Scholar 

  • Maugeri A, Klevering BJ, Rohrschneider K, Blankenagel A, Brunner HG, Deutman AF, Hoyng CB, Cremers FP (2000) Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy. Am J Hum Genet 67:960–966

    Article  PubMed  CAS  Google Scholar 

  • Maw MA, Kennedy B, Knight A, Bridges R, Roth KE, Mani EJ, Mukkadan JK, Nancarrow D, Crabb JW, Denton MJ (1997) Mutation of the gene encoding cellular retinaldehyde-binding protein in autosomal recessive retinitis pigmentosa. Nat Genet 17:198–200

    Article  PubMed  CAS  Google Scholar 

  • McHenry CL, Liu Y, Feng W, Nair AR, Feathers KL, Ding X, Gal A, Vollrath D, Sieving PA, Thompson DA (2004) MERTK arginine-844-cysteine in a patient with severe rod-cone dystrophy: loss of mutant protein function in transfected cells. Invest Ophthalmol Vis Sci 45:1456–1463

    Article  PubMed  Google Scholar 

  • McLaughlin ME, Sandberg MA, Berson EL, Dryja TP (1993) Recessive mutations in the gene encoding the beta-subunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nat Genet 4:130–134

    Article  PubMed  CAS  Google Scholar 

  • Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, Dryja TP (1998) Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. Proc Natl Acad Sci USA 95:3088–3093

    Article  PubMed  CAS  Google Scholar 

  • Morimura H, Saindelle-Ribeaudeau F, Berson EL, Dryja TP (1999) Mutations in RGR, encoding a light-sensitive opsin homologue, in patients with retinitis pigmentosa. Nat Genet 23:393–394

    Article  PubMed  CAS  Google Scholar 

  • Nakazawa M, Wada Y, Tamai M (1998) Arrestin gene mutations in autosomal recessive retinitis pigmentosa. Arch Ophthalmol 116:498–501

    PubMed  CAS  Google Scholar 

  • Nasonkin I, Illing M, Koehler MR, Schmid M, Molday RS, Weber BH (1998) Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21-p22.1 and identification of novel mutations in Stargardt’s disease. Hum Genet 102:21–26

    Article  PubMed  CAS  Google Scholar 

  • Paloma E, Coco R, Martinez-Mir A, Vilageliu L, Balcells S, Gonzalez-Duarte R (2002) Analysis of ABCA4 in mixed Spanish families segregating different retinal dystrophies. Hum Mutat 20:476

    Article  PubMed  Google Scholar 

  • Radu RA, Mata NL, Nusinowitz S, Liu X, Sieving PA, Travis GH (2003) Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt’s macular degeneration. Proc Natl Acad Sci USA 100:4742–4747

    Article  PubMed  CAS  Google Scholar 

  • Rivolta C, Sweklo EA, Berson EL, Dryja TP (2000) Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss. Am J Hum Genet 66:1975–1978

    Article  PubMed  CAS  Google Scholar 

  • Rosenfeld PJ, Cowley GS, McGee TL, Sandberg MA, Berson EL, Dryja TP (1992) A null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa. Nat Genet 1:209–213

    Article  PubMed  CAS  Google Scholar 

  • Rozet JM, Gerber S, Ghazi I, Perrault I, Ducroq D, Souied E, Cabot A, Dufier JL, Munnich A, Kaplan J (1999) Mutations of the retinal specific ATP binding transporter gene (ABCR) in a single family segregating both autosomal recessive retinitis pigmentosa RP19 and Stargardt disease: evidence of clinical heterogeneity at this locus. J Med Genet 36:447–451

    PubMed  CAS  Google Scholar 

  • Rudolph G, Kalpadakis P, Haritoglou C, Rivera A, Weber BH (2002) [Mutations in the ABCA4 gene in a family with Stargardt’s disease and retinitis pigmentosa (STGD1/RP19)]. Klin Monatsbl Augenheilkd 219:590–596

    Article  PubMed  Google Scholar 

  • Ruiz A, Borrego S, Marcos I, Antinolo G (1998) A major locus for autosomal recessive retinitis pigmentosa on 6q, determined by homozygosity mapping of chromosomal regions that contain gamma-aminobutyric acid-receptor clusters. Am J Hum Genet 62:1452–1459

    Article  PubMed  CAS  Google Scholar 

  • Schaffer AA, Gupta SK, Shriram K, Cottingham RW (1994) Avoiding recomputation in genetic linkage analysis. Hum Hered 44:225–237

    PubMed  CAS  Google Scholar 

  • Shroyer NF, Lewis RA, Yatsenko AN, Lupski JR (2001) Null missense ABCR (ABCA4) mutations in a family with stargardt disease and retinitis pigmentosa. Invest Ophthalmol Vis Sci 42:2757–2761

    PubMed  CAS  Google Scholar 

  • Simonelli F, Testa F, Zernant J, Nesti A, Rossi S, Rinaldi E, Allikmets R (2004) Association of a homozygous nonsense mutation in the ABCA4 (ABCR) gene with cone-rod dystrophy phenotype in an Italian family. Ophthalmic Res 36:82–88

    Article  PubMed  CAS  Google Scholar 

  • Small KW, Gehrs K (1996) Clinical study of a large family with autosomal dominant progressive cone degeneration. Am J Ophthalmol 121:1–12

    PubMed  CAS  Google Scholar 

  • Smith RJH, Holcomb JD, Daiger SP, Caskey CT, Pelias MZ, Alford BR, Fontenot DD, Hejtmancik JF (1989) Exclusion of Usher syndrome gene from much of chromosome 4. Cytogenet Cell Genet 50:102–106

    Article  PubMed  CAS  Google Scholar 

  • Thompson DA, Li Y, McHenry CL, Carlson TJ, Ding X, Sieving PA, Apfelstedt-Sylla E, Gal A (2001) Mutations in the gene encoding lecithin retinol acyltransferase are associated with early-onset severe retinal dystrophy. Nat Genet 28:123–124

    Article  PubMed  CAS  Google Scholar 

  • Tuson M, Marfany G, Gonzalez-Duarte R (2004) Mutation of CERKL, a novel human ceramide kinase gene, causes autosomal recessive retinitis pigmentosa (RP26). Am J Hum Genet 74:128–138

    Article  PubMed  CAS  Google Scholar 

  • Vikkula M, Mariman EC, Lui VC, Zhidkova NI, Tiller GE, Goldring MB, van Beersum SE, Waal Malefijt MC, van den Hoogen FH, Ropers HH, . (1995) Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. Cell 80:431–437

    Article  PubMed  CAS  Google Scholar 

  • Webster AR, Heon E, Lotery AJ, Vandenburgh K, Casavant TL, Oh KT, Beck G, Fishman GA, Lam BL, Levin A, Heckenlively JR, Jacobson SG, Weleber RG, Sheffield VC, Stone EM (2001) An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci 42:1179–1189

    PubMed  CAS  Google Scholar 

  • Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH (1999) Insights into the function of Rim protein in photoreceptors and etiology of Stargardt’s disease from the phenotype in abcr knockout mice. Cell 98:13–23

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the families for their participation in this study. We sincerely thank the staff of Lyton Rehmatullah Benevolent Trust (LRBT) Hospital and in particular Dr. Z. A. Qazi and Dr. M. Amer for the identification of the families, their expert clinical evaluation of affected individual and for other help. We also thank Dr. Xiaodong Jiao, Ms. Afshan Yasmeen, Mr. M. Awais and Mr. Amer Niazi for their technical help. A part of the study carried out in Pakistan was supported by Higher Education Commission, Islamabad, Pakistan and Ministry of Science & Technology, Islamabad, Pakistan. Dr. Qingjiong Zhang gratefully acknowledges the support from the National 863 Plan of China (Z19-01-04-02).

Author information

Authors and Affiliations

  1. Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Building 10, Room 10B10, 10 center Drive, MSC 1860, Bethesda, MD, 20892-1860, USA

    Qingjiong Zhang, Xueshan Xiao, S. Amer Riazuddin, Raphael Caruso, Paul A. Sieving & J. Fielding Hejtmancik

  2. National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan

    Fareeha Zulfiqar, Farooq Sabar & Sheikh Riazuddin

  3. Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China

    Qingjiong Zhang & Xueshan Xiao

  4. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, 48105, USA

    Radha Ayyagari

Authors
  1. Qingjiong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fareeha Zulfiqar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xueshan Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Amer Riazuddin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Radha Ayyagari
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Farooq Sabar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Raphael Caruso
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paul A. Sieving
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sheikh Riazuddin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J. Fielding Hejtmancik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Fielding Hejtmancik.

Additional information

Qingjiong Zhang, Fareeha Zulfiqar, Xueshan Xiao, Sheikh Riazuddin and J. Fielding Hejtmancik have contributed equally to this manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Q., Zulfiqar, F., Xiao, X. et al. Severe autosomal recessive retinitis pigmentosa maps to chromosome 1p13.3–p21.2 between D1S2896 and D1S457 but outside ABCA4. Hum Genet 118, 356–365 (2005). https://doi.org/10.1007/s00439-005-0054-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-005-0054-4

Keywords

Search

Navigation