Skip to main content
SpringerLink
Log in

Severe retinitis pigmentosa mapped to 4p15 and associated with a novel mutation in the PROM1 gene

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Mutation in the PROM1 gene previously has been identified in one family with retinal degeneration for which neither ERG recordings nor detailed information about visual impairment is available. A large family with multiple individuals affected by retinal degeneration was ascertained in the Punjab province of Pakistan. The visual acuity of all affected patients in the family was severely compromised beginning in early childhood. The retinal disease in this family is a severe form of retinitis pigmentosa (RP) accompanied by macular degeneration. Fundus changes advanced with age. Choriocapillaris atrophy and posterior RPE atrophy were obvious allowing visualization of the large choroidal vessels in patients over 40 years of age. Rod and cone responses on ERG recordings were extinguished in patient’s teens. A genome-wide scan mapped the disease to a 34.7 cM region of chromosome 4p14–p16 between D4S1599 and D4S405. A maximum lod score of 3.96 with D4S403 and D4S391 is seen at θ = 0. Sequence analysis of PROM1 located in the linkage interval identified a c.1726C>T homozygous transition in exon 15: resulting in p.Gln576X in the translated protein. This mutation is found in a homozygous state in all six affected individuals and was heterozygous in five of the six unaffected family members examined. The mutation was not detected in 192 chromosomes of unrelated control individuals of the same ethnicity and from the same region. This delineates the phenotypic characteristics of retinopathy caused by mutations in PROM1.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Boughman JA, Conneally PM, Nance WE (1980) Population genetic studies of retinitis pigmentosa. Am J Hum Genet 32:223–235

    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 

  • 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 

  • Fargeas CA, Huttner WB, Corbeil D (2007) Nomenclature of prominin-1 (CD133) splice variants-an update. Tissue Antigens 69:602–606

    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 

  • 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 

  • Hentze MW, Kulozik AE (1999) A perfect message: RNA surveillance and nonsense-mediated decay. Cell 96:307–310

    Article  PubMed  CAS  Google Scholar 

  • Jaszai J, Fargeas CA, Florek M, Huttner WB, Corbeil D (2006) Focus on Molecules: Prominin-1 (CD133). Exp Eye Res

  • 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 

  • Kniazeva M, Chiang MF, Morgan B, Anduze AL, Zack DJ, Han M, Zhang K (1999) A new locus for autosomal dominant stargardt-like disease maps to chromosome 4. Am J Hum Genet 64:1394–1399

    Article  PubMed  CAS  Google Scholar 

  • Li A, Jiao X, Munier FL, Schorderet DF, Yao W, Iwata F, Hayakawa M, Kanai A, Shy Chen M, Alan Lewis R, Heckenlively J, Weleber RG, Traboulsi EI, Zhang Q, Xiao X, Kaiser-Kupfer M, Sergeev YV, Hejtmancik JF (2004) Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2. Am J Hum Genet 74:817–826

    Article  PubMed  CAS  Google Scholar 

  • Marmor MF, Holder GE, Seeliger MW, Yamamoto S (2004) Standard for clinical electroretinography (2004 update). Doc Ophthalmol 108:107–114

    Article  PubMed  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 

  • Maw MA, Corbeil D, Koch J, Hellwig A, Wilson-Wheeler JC, Bridges RJ, Kumaramanickavel G, John S, Nancarrow D, Roper K, Weigmann A, Huttner WB, Denton MJ (2000) A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol Genet 9:27–34

    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 

  • Michaelides M, Hunt DM, Moore AT (2003a) The genetics of inherited macular dystrophies. J Med Genet 40:641–650

    Article  PubMed  CAS  Google Scholar 

  • Michaelides M, Johnson S, Poulson A, Bradshaw K, Bellmann C, Hunt DM, Moore AT (2003b) An autosomal dominant bull’s-eye macular dystrophy (MCDR2) that maps to the short arm of chromosome 4. Invest Ophthalmol Vis Sci 44:1657–1662

    Article  PubMed  Google Scholar 

  • Miraglia S, Godfrey W, Yin AH, Atkins K, Warnke R, Holden JT, Bray RA, Waller EK, Buck DW (1997) A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood 90:5013–5021

    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 

  • 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 

  • Weigmann A, Corbeil D, Hellwig A, Huttner WB (1997) Prominin, a novel microvilli-specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non-epithelial cells. Proc Natl Acad Sci USA 94:12425–12430

    Article  PubMed  CAS  Google Scholar 

  • Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG, Olweus J, Kearney J, Buck DW (1997) AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 90:5002–5012

    PubMed  CAS  Google Scholar 

  • Zelhof AC, Hardy RW, Becker A, Zuker CS (2006) Transforming the architecture of compound eyes. Nature 443:696–699

    Article  PubMed  CAS  Google Scholar 

  • Zhang Q, Zulfiqar F, Xiao X, Amer Riazuddin S, Ayyagari R, Sabar F, Caruso R, Sieving PA, Riazuddin S, Fielding Hejtmancik J (2005) Severe autosomal recessive retinitis pigmentosa maps to chromosome 1p13.3–p21.2 between D1S2896 and D1S457 but outside ABCA4. Hum Genet 118:356–365

    Article  PubMed  CAS  Google Scholar 

  • Zhang Q, Li S, Xiao X, Jia X, Guo X (2007) The 208delG mutation in FSCN2 does not associate with retinal degeneration in Chinese individuals. Invest Ophthalmol Vis Sci 48:530–533

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to the families for their participation in this study. We sincerely thank the staff of Lyton Rehmatullah Benevolent Trust (LRBT) Hospital for the identification of the families and collection of clinical information. We also thank Ms. Afshan Yasmeen, Ms. Shagufta Begum, and Mr. Farooq Sabar for their technical help. Dr. Qingjiong Zhang is a recipient of Fok Ying Tung Education Foundation (6041) and of a fund from National Natural Science Foundation of China (30572006 to QZ).

Author information

Authors and Affiliations

  1. Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, 20982, USA

    Qingjiong Zhang, S. Amer Riazuddin, Raphael Caruso, Ian MacDonald, Paul Sieving & J. Fielding Hejtmancik

  2. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou, 510060, People’s Republic of China

    Qingjiong Zhang & Xueshan Xiao

  3. National Center of Excellence in Molecular Biology, University of Punjab, 87-West Canal Bank Road, Thokar Niaz Baig, Lahore, 53700, Pakistan

    Fareeha Zulfiqar, S. Amer Riazuddin, Zahoor Ahmad & Sheikh Riazuddin

  4. OGCSB/NEI/NIH, Building 10, Room 10B10, 10 Center Drive, MSC 1860, Bethesda, MD, 20892-1860, USA

    J. Fielding Hejtmancik

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. Zahoor Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Raphael Caruso
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ian MacDonald
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paul 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 authors

Correspondence to Qingjiong Zhang, Sheikh Riazuddin or J. Fielding Hejtmancik.

Additional information

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

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Q., Zulfiqar, F., Xiao, X. et al. Severe retinitis pigmentosa mapped to 4p15 and associated with a novel mutation in the PROM1 gene. Hum Genet 122, 293–299 (2007). https://doi.org/10.1007/s00439-007-0395-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-007-0395-2

Keywords

Search

Navigation