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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1999 Apr;64(4):1024–1035. doi: 10.1086/302323

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.

A Maugeri 1, M A van Driel 1, D J van de Pol 1, B J Klevering 1, F J van Haren 1, N Tijmes 1, A A Bergen 1, K Rohrschneider 1, A Blankenagel 1, A J Pinckers 1, N Dahl 1, H G Brunner 1, A F Deutman 1, C B Hoyng 1, F P Cremers 1
PMCID: PMC1377826  PMID: 10090887

Abstract

In 40 western European patients with Stargardt disease (STGD), we found 19 novel mutations in the retina-specific ATP-binding cassette transporter (ABCR) gene, illustrating STGD's high allelic heterogeneity. One mutation, 2588G-->C, identified in 15 (37.5%) patients, shows linkage disequilibrium with a rare polymorphism (2828G-->A) in exon 19, suggesting a founder effect. The guanine at position 2588 is part of the 3' splice site of exon 17. Analysis of the lymphoblastoid cell mRNA of two STGD patients with the 2588G-->C mutation shows that the resulting mutant ABCR proteins either lack Gly863 or contain the missense mutation Gly863Ala. We hypothesize that the 2588G-->C alteration is a mild mutation that causes STGD only in combination with a severe ABCR mutation. This is supported in that the accompanying ABCR mutations in at least five of eight STGD patients are null (severe) and that a combination of two mild mutations has not been observed among 68 STGD patients. The 2588G-->C mutation is present in 1 of every 35 western Europeans, a rate higher than that of the most frequent severe autosomal recessive mutation, the cystic fibrosis conductance regulator gene mutation DeltaPhe508. Given an STGD incidence of 1/10,000, homozygosity for the 2588G-->C mutation or compound heterozygosity for this and other mild ABCR mutations probably does not result in an STGD phenotype.

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Selected References

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  1. Allikmets R., Shroyer N. F., Singh N., Seddon J. M., Lewis R. A., Bernstein P. S., Peiffer A., Zabriskie N. A., Li Y., Hutchinson A. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science. 1997 Sep 19;277(5333):1805–1807. doi: 10.1126/science.277.5333.1805. [DOI] [PubMed] [Google Scholar]
  2. Allikmets R., Singh N., Sun H., Shroyer N. F., Hutchinson A., Chidambaram A., Gerrard B., Baird L., Stauffer D., Peiffer A. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997 Mar;15(3):236–246. doi: 10.1038/ng0397-236. [DOI] [PubMed] [Google Scholar]
  3. Anderson K. L., Baird L., Lewis R. A., Chinault A. C., Otterud B., Leppert M., Lupski J. R. A YAC contig encompassing the recessive Stargardt disease gene (STGD) on chromosome 1p. Am J Hum Genet. 1995 Dec;57(6):1351–1363. [PMC free article] [PubMed] [Google Scholar]
  4. Azarian S. M., Megarity C. F., Weng J., Horvath D. H., Travis G. H. The human photoreceptor rim protein gene (ABCR): genomic structure and primer set information for mutation analysis. Hum Genet. 1998 Jun;102(6):699–705. doi: 10.1007/s004390050765. [DOI] [PubMed] [Google Scholar]
  5. Azarian S. M., Travis G. H. The photoreceptor rim protein is an ABC transporter encoded by the gene for recessive Stargardt's disease (ABCR). FEBS Lett. 1997 Jun 9;409(2):247–252. doi: 10.1016/s0014-5793(97)00517-6. [DOI] [PubMed] [Google Scholar]
  6. Cremers F. P., van de Pol D. J., van Driel M., den Hollander A. I., van Haren F. J., Knoers N. V., Tijmes N., Bergen A. A., Rohrschneider K., Blankenagel A. Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR. Hum Mol Genet. 1998 Mar;7(3):355–362. doi: 10.1093/hmg/7.3.355. [DOI] [PubMed] [Google Scholar]
  7. Denoyelle F., Weil D., Maw M. A., Wilcox S. A., Lench N. J., Allen-Powell D. R., Osborn A. H., Dahl H. H., Middleton A., Houseman M. J. Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol Genet. 1997 Nov;6(12):2173–2177. doi: 10.1093/hmg/6.12.2173. [DOI] [PubMed] [Google Scholar]
  8. Estivill X., Fortina P., Surrey S., Rabionet R., Melchionda S., D'Agruma L., Mansfield E., Rappaport E., Govea N., Milà M. Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet. 1998 Feb 7;351(9100):394–398. doi: 10.1016/S0140-6736(97)11124-2. [DOI] [PubMed] [Google Scholar]
  9. Gerber S., Rozet J. M., Bonneau D., Souied E., Camuzat A., Dufier J. L., Amalric P., Weissenbach J., Munnich A., Kaplan J. A gene for late-onset fundus flavimaculatus with macular dystrophy maps to chromosome 1p13. Am J Hum Genet. 1995 Feb;56(2):396–399. [PMC free article] [PubMed] [Google Scholar]
  10. Gerber S., Rozet J. M., van de Pol T. J., Hoyng C. B., Munnich A., Blankenagel A., Kaplan J., Cremers F. P. Complete exon-intron structure of the retina-specific ATP binding transporter gene (ABCR) allows the identification of novel mutations underlying Stargardt disease. Genomics. 1998 Feb 15;48(1):139–142. doi: 10.1006/geno.1997.5164. [DOI] [PubMed] [Google Scholar]
  11. Hoyng C. B., Poppelaars F., van de Pol T. J., Kremer H., Pinckers A. J., Deutman A. F., Cremers F. P. Genetic fine mapping of the gene for recessive Stargardt disease. Hum Genet. 1996 Oct;98(4):500–504. doi: 10.1007/s004390050247. [DOI] [PubMed] [Google Scholar]
  12. Huber I., Bitner-Glindzicz M., de Kok Y. J., van der Maarel S. M., Ishikawa-Brush Y., Monaco A. P., Robinson D., Malcolm S., Pembrey M. E., Brunner H. G. X-linked mixed deafness (DFN3): cloning and characterization of the critical region allows the identification of novel microdeletions. Hum Mol Genet. 1994 Jul;3(7):1151–1154. doi: 10.1093/hmg/3.7.1151. [DOI] [PubMed] [Google Scholar]
  13. Kaplan J., Gerber S., Larget-Piet D., Rozet J. M., Dollfus H., Dufier J. L., Odent S., Postel-Vinay A., Janin N., Briard M. L. A gene for Stargardt's disease (fundus flavimaculatus) maps to the short arm of chromosome 1. Nat Genet. 1993 Nov;5(3):308–311. doi: 10.1038/ng1193-308. [DOI] [PubMed] [Google Scholar]
  14. Klugbauer N., Hofmann F. Primary structure of a novel ABC transporter with a chromosomal localization on the band encoding the multidrug resistance-associated protein. FEBS Lett. 1996 Aug 5;391(1-2):61–65. doi: 10.1016/0014-5793(96)00700-4. [DOI] [PubMed] [Google Scholar]
  15. Luciani M. F., Denizot F., Savary S., Mattei M. G., Chimini G. Cloning of two novel ABC transporters mapping on human chromosome 9. Genomics. 1994 May 1;21(1):150–159. doi: 10.1006/geno.1994.1237. [DOI] [PubMed] [Google Scholar]
  16. Martínez-Mir A., Bayés M., Vilageliu L., Grinberg D., Ayuso C., del Río T., García-Sandoval B., Bussaglia E., Baiget M., Gonzàlez-Duarte R. A new locus for autosomal recessive retinitis pigmentosa (RP19) maps to 1p13-1p21. Genomics. 1997 Feb 15;40(1):142–146. doi: 10.1006/geno.1996.4528. [DOI] [PubMed] [Google Scholar]
  17. Martínez-Mir A., Paloma E., Allikmets R., Ayuso C., del Rio T., Dean M., Vilageliu L., Gonzàlez-Duarte R., Balcells S. Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR. Nat Genet. 1998 Jan;18(1):11–12. doi: 10.1038/ng0198-11. [DOI] [PubMed] [Google Scholar]
  18. Noble K. G., Carr R. E. Stargardt's disease and fundus flavimaculatus. Arch Ophthalmol. 1979 Jul;97(7):1281–1285. doi: 10.1001/archopht.1979.01020020023005. [DOI] [PubMed] [Google Scholar]
  19. Peelen T., van Vliet M., Petrij-Bosch A., Mieremet R., Szabo C., van den Ouweland A. M., Hogervorst F., Brohet R., Ligtenberg M. J., Teugels E. A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families. Am J Hum Genet. 1997 May;60(5):1041–1049. [PMC free article] [PubMed] [Google Scholar]
  20. Petrij-Bosch A., Peelen T., van Vliet M., van Eijk R., Olmer R., Drüsedau M., Hogervorst F. B., Hageman S., Arts P. J., Ligtenberg M. J. BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet. 1997 Nov;17(3):341–345. doi: 10.1038/ng1197-341. [DOI] [PubMed] [Google Scholar]
  21. Rozet J. M., Gerber S., Souied E., Perrault I., Châtelin S., Ghazi I., Leowski C., Dufier J. L., Munnich A., Kaplan J. Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies. Eur J Hum Genet. 1998 May-Jun;6(3):291–295. doi: 10.1038/sj.ejhg.5200221. [DOI] [PubMed] [Google Scholar]
  22. Shapiro M. B., Senapathy P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 1987 Sep 11;15(17):7155–7174. doi: 10.1093/nar/15.17.7155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Shuber A. P., Skoletsky J., Stern R., Handelin B. L. Efficient 12-mutation testing in the CFTR gene: a general model for complex mutation analysis. Hum Mol Genet. 1993 Feb;2(2):153–158. doi: 10.1093/hmg/2.2.153. [DOI] [PubMed] [Google Scholar]
  24. Tuerlings J. H., Mol B., Kremer J. A., Looman M., Meuleman E. J., te Meerman G. J., Buys C. H., Merkus H. M., Scheffer H. Mutation frequency of cystic fibrosis transmembrane regulator is not increased in oligozoospermic male candidates for intracytoplasmic sperm injection. Fertil Steril. 1998 May;69(5):899–903. doi: 10.1016/s0015-0282(98)00050-8. [DOI] [PubMed] [Google Scholar]
  25. Weber B. H., Sander S., Kopp C., Walker D., Eckstein A., Wissinger B., Zrenner E., Grimm T. Analysis of 21 Stargardt's disease families confirms a major locus on chromosome 1p with evidence for non-allelic heterogeneity in a minority of cases. Br J Ophthalmol. 1996 Aug;80(8):745–749. doi: 10.1136/bjo.80.8.745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. de Kok Y. J., van der Maarel S. M., Bitner-Glindzicz M., Huber I., Monaco A. P., Malcolm S., Pembrey M. E., Ropers H. H., Cremers F. P. Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4. Science. 1995 Feb 3;267(5198):685–688. doi: 10.1126/science.7839145. [DOI] [PubMed] [Google Scholar]
  27. van Driel M. A., Maugeri A., Klevering B. J., Hoyng C. B., Cremers F. P. ABCR unites what ophthalmologists divide(s) Ophthalmic Genet. 1998 Sep;19(3):117–122. doi: 10.1076/opge.19.3.117.2187. [DOI] [PubMed] [Google Scholar]

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