Journal Mobile Options
Table of Contents
Vol. 37, No. 3, 2005
Issue release date: May–June 2005

Genotype-Phenotype Correlation in Italian Families with Stargardt Disease

Simonelli F. · Testa F. · Zernant J. · Nesti A. · Rossi S. · Allikmets R. · Rinaldi E.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password





Contact Information











I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Abstract

Autosomal recessive Stargardt disease (STGD) has been associated with substantial genetic and phenotypic heterogeneity. By systematic clinical analyses of STGD patients with complete genetic data (i.e. identified mutations on both alleles of the ABCA4 gene), we set out to determine phenotypic subtypes and to correlate these with specific ABCA4 alleles. Twenty-eight patients from 18 families with STGD/fundus flavimaculatus were investigated. All patients were submitted to complete ophthalmologic examination, electrophysiology, fluorescein angiography and ABCA4 gene chip analysis. Two main clinical phenotypes were observed among the examined patients. The severe phenotype was characterized by the onset of the disease <20 years and reduced ERG response, whereas the mild phenotype presented with later onset of the disease and a normal ERG response. Genetic analysis of the ABCA4 gene revealed, in the severe group, more frequently deletions, stop codons and insertions as compared to the mild phenotype group (p = 0.0113 by Fisher’s exact test). Moreover, the compound heterozygous mutations G1961E/5018 + 2T → C found in 7 patients from 3 unrelated STGD families were associated with a mild phenotype in all subjects, except 1. This study documented variability of the clinical expression of STGD in relation to the age of onset of the disease, fundus appearance and the ERG response and allowed to subdivide patients into a severe and a mild phenotype group. These findings suggest that an extensive and comprehensive genetic analysis of STGD patients combined with thorough clinical evaluation, including the careful recording of the age of onset of the disease, would allow a more precise prognostic evaluation.



Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Deutman AF, Hoyng CB: Macular dystrophies; in Ryan SJ (ed): Retina. St Louis, Mosby, 2001, pp 1219–1223.
  2. Zhang K, Kniazeva M, Han M, Li W, Yu Z, Yang Z, Li Y, Metzker ML, Allikmets R, Zack DJ, Kakuk LE, Lagali PS, Wong PW, MacDonald IM, Sieving PA, Figueroa DJ, Austin CP, Gould RJ, Ayyagari R, Petrukhin K: A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet 2001;27:89–93.
  3. Kaplan J, Gerber S, Larget-Piet D, Rozet JM, Dollfus H, Dufier JL, Odent S, Postel-Vinay A, Janin N, Briard ML, et al: A gene for Stargardt’s disease (fundus flavimaculatus) maps to the short arm of chromosome 1. Nat Genet 1993;5:308–311.
  4. 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: A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 1997;15:236–246.
  5. Molday LL, Rabin AR, Molday RS: ABCR expression in foveal cone photoreceptors and its role in Stargardt macular dystrophy. Nat Genet 2000;25:257–258.
  6. Sun H, Smallwood PM, Nathans J: Biochemical defects in ABCR protein variants associated with human retinopathies. Nat Genet 2000;26:242–246.
  7. 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: Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt’s disease gene ABCR. Hum Mol Genet 1998;7:355–362.
  8. Martinez-Mir A, Paloma E, Allikmets R, Ayuso C, del Rio T, Dean M, Vilageliu L, Gonzalez-Duarte R, Balcells S: Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR. Nat Genet 1998;18:11–12.
  9. Rozet JM, Gerber S, Ghazi I, Perrault I, Ducroq D, Souied E, Cabot A, Dufier JL, Munnich A, Kaplan J: 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 1999;36:447–451.
  10. Maugeri A, Klevering BJ, Rohrschneider K, Blankenagel A, Brunner HG, Deutman AF, Hoyng CB, Cremers FP: Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy. Am J Hum Genet 2000;67:960–966.
  11. 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: ABCA4 gene mutations in Japanese patients with Stargardt disease and retinitis pigmentosa. Invest Ophthalmol Vis Sci 2002;43:2819–2824.
  12. Fishman GA, Stone EM, Grover S, Derlacki DJ, Haines HL, Hockey RR: Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene. Arch Ophthalmol 1999;117:504–510.
  13. Lois N, Holder GE, Bunce C, Fitzke FW, Bird AC: Phenotypic subtypes of Stargardt macular dystrophy-fundus flavimaculatus. Arch Ophthalmol 2001;119:359–369.
  14. Klevering BJ, van Driel M, van de Pol DJ, Pinckers AJ, Cremers FP, Hoyng CB: Phenotypic variations in a family with retinal dystrophy as result of different mutations in the ABCR gene. Br J Ophthalmol 1999;83:914–918.
  15. Lewis RA, Shroyer NF, Singh N, Allikmets R, Hutchinson A, Li Y, Lupski JR, Leppert M, Dean M: Genotype/phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. Am J Hum Genet 1999;64:422–434.
  16. Papaioannou M, Ocaka L, Bessant D, Lois N, Bird A, Payne A, Bhattacharya S: An analysis of ABCR mutations in British patients with recessive retinal dystrophies. Invest Ophthalmol Vis Sci 2000;41:16–19.
  17. Rivera A, White K, Stohr H, Steiner K, Hemmrich N, Grimm T, Jurklies B, Lorenz B, Scholl HP, Apfelstedt-Sylla E, Weber BH: A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet 2000;67:800–813.
  18. Simonelli F, Testa F, de Crecchio G, Rinaldi E, Hutchinson A, Atkinson A, Dean M, D’Urso M, Allikmets R: New ABCR mutations and clinical phenotype in Italian patients with Stargardt disease. Invest Ophthalmol Vis Sci 2000;41:892–897.
  19. Briggs CE, Rucinski D, Rosenfeld PJ, Hirose T, Berson EL, Dryja TP: Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration. Invest Ophthalmol Vis Sci 2001;42:2229–2236.
  20. Shroyer NF, Lewis RA, Yatsenko AN, Lupski JR: Null missense ABCR (ABCA4) mutations in a family with Stargardt disease and retinitis pigmentosa. Invest Ophthalmol Vis Sci 2001;42:2757–2761.
  21. Shroyer NF, Lewis RA, Yatsenko AN, Wensel TG, Lupski JR: Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration. Hum Mol Genet 2001;10:2671–2678.
  22. Gerth C, Andrassi-Darida M, Bock M, Preising MN, Weber BH, Lorenz B: Phenotypes of 16 Stargardt macular dystrophy/fundus flavimaculatus patients with known ABCA4 mutations and evaluation of genotype-phenotype correlation. Graefes Arch Clin Exp Ophthalmol 2002;240:628–638.
  23. Fumagalli A, Ferrari M, Soriani N, Gessi A, Foglieni B, Martina E, Manitto MP, Brancato R, Dean M, Allikmets R, Cremonesi L: Mutational scanning of the ABCR gene with double-gradient denaturing-gradient gel electrophoresis (DG-DGGE) in Italian Stargardt disease patients. Hum Genet 2001;109:326–338.
  24. Cideciyan AV, Aleman TS, Swider M, Schwartz SB, Steinberg JD, Brucker AJ, Maguire AM, Bennett J, Stone EM, Jacobson SG: Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cycle: A reappraisal of the human disease sequence. Hum Mol Genet 2004;13:525–534.
  25. Marmor MF, Zrenner E: Standard for clinical electroretinography. International Society for Clinical Electrophysiology of Vision. Doc Ophthalmol 1998–99;97:143–156.
  26. 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: Genotyping microarray (gene chip) for the ABCR (ABCA4) gene. Hum Mutat 2003;22:395–403.
  27. Kurg A, Tonisson N, Georgiou I, Shumaker J, Tollett J, Metspalu A: Arrayed primer extension: Solid-phase four-color DNA resequencing and mutation detection technology. Genet Test 2000;4:1–7.
  28. Tonisson N, Zernant J, Kurg A, Pavel H, Slavin G, Roomere H, Meiel A, Hainaut P, Metspalu A: Evaluating the arrayed primer extension resequencing assay of TP53 tumor suppressor gene. Proc Natl Acad Sci USA 2002;99:5503–5508.
  29. Paloma E, Martinez-Mir A, Vilageliu L, Gonzalez-Duarte R, Balcells S: Spectrum of ABCA4 (ABCR) gene mutations in Spanish patients with autosomal recessive macular dystrophies. Hum Mutat 2001;17:504–510.
  30. Guymer RH, Heon E, Lotery AJ, Munier FL, Schorderet DF, Baird PN, McNeil RJ, Haines H, Sheffield VC, Stone EM: Variation of codons 1961 and 2177 of the Stargardt disease gene is not associated with age-related macular degeneration. Arch Ophthalmol 2001;119:745–751.
  31. Armstrong JD, Meyer D, Xu S, Elfervig JL: Long-term follow-up of Stargardt’s disease and fundus flavimaculatus. Ophthalmology 1998;105:448–457.
  32. Rotenstreich Y, Fishman GA, Anderson RJ: Visual acuity loss and clinical observations in a large series of patients with Stargardt disease. Ophthalmology 2003;110:1151–1158.
  33. Lois N, Holder GE, Fitzke FW, Plant C, Bird AC: Intrafamilial variation of phenotype in Stargardt macular dystrophy-fundus flavimaculatus. Invest Ophthalmol Vis Sci 1999;40:2668–2675.


Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50