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Leber Congenital Amaurosis — Genotyping Required for Possible Inclusion in a Clinical Trial

  • Isabelle Perrault
  • Sylvie Gerber
  • Sylvain Hanein
  • Serge Picaud
  • Jean-Michel Rozet
  • Jean-Louis Dufier
  • Arnold Munnich
  • José Sahel
  • Josseline Kaplan
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 533)

Abstract

The genetic heterogeneity of LCA no longer needs to be demonstrated. Indeed, the six already known disease-causing genes and the two additional LCA loci only account for 45% of all patients. To this tremendous genetic heterogeneity corresponds an almost equivalent physiopathological heterogeneity and to a minor extent a clinical variability. Therefore, the identification of LCA-causing genes and subsequent genotyping is an obligatory prerequisite to classify patients and include them in clinical trials. For this reason, we have collected several consanguineous multiplex families affected with LCA and performed a genome-wide search for homozygosity. Three distinct chromosomal regions, different from the 8 already known LCA loci, have been identified for three unrelated families. The candidate genes lying in these regions are currently analyzed. On the other hand, very recently, encouraging therapeutic trials have been performed in order to propose gene therapy to the RPE65 subgroup. Nevertheless, to date in Europe, the major LCA gene is GUCY2D. It is why it seems important to us to develop a therapeutic approach for this group. A murine retinal explant model of pharmacological-induced GUCY2D deficiency is currently developed in our group. This model will be of primary importance to screen different drugs for their ability to slow, stop or reverse the phenotype.

Keywords

Retinitis Pigmentosa Visual Cycle Retinitis Pigmentosa GTPase Regulator Kinase Homology Domain Single Heterozygote 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Hollander, A.I., Heckenlively, J.R., Born, L.I., Kok, Y.J.M., Velde-Visser, S.D., Kellner, U., Jurklies, B., Schooneveld, M.J., Blankenagel, A., Rohrschneider, K. et al., 2001, Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the Crumbs homologue 1 (CRBI) gene. Am. J. Hum. Genet. 69:198–203.CrossRefGoogle Scholar
  2. Dharmaraj, S.Y., Robitaille, J.M., Silva, E., Zhu, D., Mitchell, T.N., Maltby, L.P., Baffoe-Bonnie, A.B. and Maumenee, I.H., 2000, A novel locus for Leber congenital amaurosis maps to chromosome 6q. Am. J. Hum. Genet. 66:319–326.PubMedCrossRefGoogle Scholar
  3. Dryja, T.P., Adams, S.M., Grimsby, J.L., McGee, T.L., Hong, T., Andréasson, S. and Berson, E.L., 2001, Null RPGRIPI alleles in patients with Leber congenital amaurosis. Am. J. Hum. Genet. 68:1295–1298.PubMedCrossRefGoogle Scholar
  4. Frasson, M., Sahel, J.A., Fabre, M., Simonutti, M., Dreyfus, H. and Picaud, S., 1999, Retinitis pigmentosa: rod photoreceptor rescue by a calcium-channel blocker in the rd mouse. Nat. Med., 5,1183–1187PubMedCrossRefGoogle Scholar
  5. Freund, C.L., Wang, Q.-L., Chen, S., Muskat, B.L., Wiles, C.D., Sheffield, V.C., Jacobson, S.G., McInnes, R.R., Zack, D.J. and Stone, E.M., 1998, De novo mutations in the CRX homeobox gene associated with Leber congenital amaurosis. Nat. Genet., 18:311–312.PubMedCrossRefGoogle Scholar
  6. Furukawa, T., Morrow, E.M. and Cepko, C.L., 1997, Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation. Cell 91:531–541PubMedCrossRefGoogle Scholar
  7. Gerber, S., Perrault, I., Hanein, S., Barbet, F., Ducroq, D., Ghazi, I., Martin-Coignard, D., Leowski, C., Homfray, T., Dufier, J.L. et al., 2001, Complete exon-intron structure of the RPGR-interacting protein (RPGRIPI) gene allows the identification of mutations underlying Leber congenital amaurosis. Eur. J. Hum. Genet. 9:561–571PubMedCrossRefGoogle Scholar
  8. Gerber S, Perrault I, Hanein S, Shalev S, Zlotogora J, Barbet F, Ducroq D, Dufier JL, Munnich A, Rozet JM, Kaplan J., 2002, A novel mutation disrupting the cytoplasmic domain of CRB I in a large consanguineous family of Palestinian origin affected with Leber congenital amaurosis. Ophthal. Genet. 22:3.Google Scholar
  9. Hong, D.H., Yue, G., Adamian, M. and Li, T., 2001, Retinitis pigmentosa GTPase regulator (RPGR)-interacting protein is stably associated with the photoreceptor ciliary axoneme and anchors RPGR to the connecting cilium. J. Biol. Chem. 276:12091–12099PubMedCrossRefGoogle Scholar
  10. Izaddoost, S., Nam, S.-C., Bhat, M.A., Bellen, H.J. and Choi, K.-W.,2002, Drosophila Crumbs is a positional cue in photoreceptor adherens junctions and rhabdomeres. Nature 416:178–183.PubMedCrossRefGoogle Scholar
  11. Lotery, A.J., Jacobson, S.G., Fishman, G.A., Weleber, R.G., Fulton, A.B., Namperumalsamy, P., Heon, E., Levin, A.V., Grover, S., Rosenow, J.R. et al., 2001, Mutations in the CRBI gene cause Leber congenital amaurosis. Arch. Ophthalmol. 119:415–420.PubMedGoogle Scholar
  12. Marlhens, F., Bareil, C., Griffoin, J.-M., Zrenner, E., Amalric, P., Eliaou, C., Liu, S.-Y., Harris, E., Redmond, T.M., Arnaud, B. et al., 1997, Mutations in RPE65 cause Leber’s congenital amaurosis. Nat. Genet.,17:139–141. PubMedCrossRefGoogle Scholar
  13. Pellikka, M., Tanentzapf, G., Pinto, M., Smith, C., McGlade, CJ., Ready, D.F. and Tepass, U., 2002, Crumbs, the Drosophila homologue of human CRBI/RPI2, is essential for photoreceptor morphogenesis. Nature 416:143–149.PubMedCrossRefGoogle Scholar
  14. Perrault, I., Rozet, J.M., Calvas, P., Gerber, S., Camuzat, A., Dollfus, H., Châtelin, S., Souied, E., Ghazi, I., Leowski, C. et al., 1996, Retinal-specific guanylate cyclase gene mutations in Leber’s congenital amaurosis. Nat. Genet. 14:461–464.PubMedCrossRefGoogle Scholar
  15. Perrault, I., Rozet, J.-M., Gerber, S., Ghazi, I., Leowski, C., Ducroq, D., Souied, E., Dufier, J.-L., Munnich, A. and Kaplan, J., 1999, Leber congenital amaurosis. Mol. Genet. Metab. 68:200–208PubMedCrossRefGoogle Scholar
  16. Perrault, I., Rozet, J.M., Gerber, S., Ghazi, I., Ducroq, D., Souied, E., Leowski, C., Bonnemaison, M., Dufier, J.L., Munnich, A. et al., 2000, Spectrum of retGCI mutations in Leber’s congenital amaurosis. Eur. J. Hum. Genet. 8:578–582.PubMedCrossRefGoogle Scholar
  17. Redmond, T.M., Yu, S., Lee, E., Bok, D., Hamasaki, D., Chen, N., Goletz, P., Ma, J.-X., Crouch, R.K. and Pfeifer, K., 1998, Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat. Genet. 20:344–351.PubMedCrossRefGoogle Scholar
  18. Roepman, R., Bernoud-Hubac, N., Schick, D., Maugeri, A., Berger, W., Ropers, H.-H., Cremers, F.P.M. and Ferreira, P.A., 2000, The Retinitis Pigmentosa GTPase Regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors. Hum. Mol. Genet. 9: 2095–2105.PubMedCrossRefGoogle Scholar
  19. Sohocki, M.M., Bowne, S.J., Sullivan, L.S., Blackshaw, S., Cepko, C.L., Payne, A.M., Bhattacharya, S.S., Khaliq, S., Mehdi, S.Q., Birch, D.G. et al., 2000, Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis. Nat. Genet. 24:79–83PubMedCrossRefGoogle Scholar
  20. Stockton, D.W., Lewis, R.A., Abboud, E.B., Al Rajhi, A., Jabak, M., Anderson, K.L. and Lupski, J.R., 1998, A novel locus for Leber congenital amaurosis on chromosome 14q24. Hum. Genet. 103:328–333.PubMedCrossRefGoogle Scholar
  21. Spuy J, Chapple JP, Clark BJ, Luthert PJ, Sethi CS, Cheetham ME., 2002, The Leber congenital amaurosis gene product AIPL1 is localized exclusively in rod photoreceptors of the adult human retina. Hum Mol Genet. 11:823–31PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Isabelle Perrault
    • 1
  • Sylvie Gerber
    • 1
  • Sylvain Hanein
    • 1
  • Serge Picaud
    • 2
  • Jean-Michel Rozet
    • 1
  • Jean-Louis Dufier
    • 3
  • Arnold Munnich
    • 1
  • José Sahel
    • 2
  • Josseline Kaplan
    • 1
  1. 1.Inserm U393Hôpital Necker Enfants MaladesParisFrance
  2. 2.Inserm U592Hôpital Saint AntoineParisFrance
  3. 3.Service d’ophthalmologieHôpital NeckerParisFrance

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