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Retinal–specific guanylate cyclase gene mutations in Leber's congenital amaurosis

Abstract

Leber's congenital amaurosis (LCA, MIM 2040001), the earliest and most severe form of inherited retinopathy, accounts for at least 5% of all inherited retinal dystrophies2,3. This autosomal recessive condition is usually recognized at birth or during the first months of life in an infant with total blindness or greatly impaired vision, normal fundus and extinguished electroretinogram (ERG4). Nystagmus (pendular type) and characteristic eye poking are frequently observed in the first months of life (digitoocular sign of Franceschetti5). Hypermetropia and keratoconus frequently develop in the course of the disease6,7. The observation by Waardenburg8 of normal children born to affected parents supports the genetic heterogeneity of LCA. Until now, however, little was known about the pathophysiology of the disease, but LCA is usually regarded as the consequence of either impaired development of photore-ceptors or extremely early degeneration of cells that have developed normally9. We have recently mapped a gene for LCA to chromosome 17p13.1 (LCA1) by homozygosity mapping in consanguineous families of North African origin and provided evidence of genetic heterogeneity in our sample, as LCA1 accounted for 8/15 LCA families in our series10,11. Here, we report two missense mutations (F589S) and two frameshift mutations (nt 460 del C, nt 693 del C) of the retinal guanylate cyclase (RETGC, GDB symbol GUC2D) gene in four unrelated LCA1 probands of North African ancestry and ascribe LCA1 to an impaired production of cGMP in the retina, with permanent closure of cGMP-gated cation channels.

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References

  1. Leber, T. Uber retinitis pigmentosa and angeborene amaurose. Graefes Arch. Klin. Exp. Ophthalmol. 15, 13–20 (1869).

    Google Scholar 

  2. Foxman, S.G., Heckenlively, J.R., Batemen, B.J. & Wirstschafter, J.D. Classification of congenital and early-onset retinitis pigmentosa. Arch. Ophthalmol. 103, 1502–1507 (1985).

    Article  CAS  Google Scholar 

  3. Kaplan, J., Bonneau, D., Frézal, J., Munnich, A. & Dufier, J.L. Clinical and genetic heterogeneity in retinitis pigmentosa. Hum. Genet. 85, 635–642 (1990).

    Article  CAS  Google Scholar 

  4. Franceschetti, A. & Dieterle, P. L'importance diagnostique de l'électrorétinogramme dans les dégénérescences tapéto-rétiniennes avec rétrécissement du champ visuel et héméralopie. Conf. Neurol. 14, 184–186 (1954).

    Article  CAS  Google Scholar 

  5. Franceschetti, A & Forni, S. Dégénérescence tapéto-rétinienne (type Leber) avec aspect marbré du fond de I'oeil périphérique. Ophthalmologies 135, 610–616 (1958).

    Article  CAS  Google Scholar 

  6. Wagner, R.S., Caputo, A.R., Nelson, L.B. & Zanoni, D. High hyperopia in Leber's congenital amaurosis. Arch. Ophthalmol. 103, 1507–1509 (1985).

    Article  CAS  Google Scholar 

  7. Karel, I. Keratoconus in congenital diffuse tapetoretinal degeneration. Ophthalomologica 155, 8–15 (1968).

    Article  CAS  Google Scholar 

  8. Waardenburg, P.J. & Schappert-Kimmijser, J. On various recessive biotypes of Leber's congenital amaurosis. Acta Ophthalmol. (Copenhagen) 41, 317–320 (1963).

    Article  CAS  Google Scholar 

  9. Mizuno, K. et al. Leber's congenital amaurosis. Am. J. Ophthalmol. 83, 32–42 (1977).

    Article  CAS  Google Scholar 

  10. Camuzat, A. et al. A gene for Leber's congenital amaurosis maps to chromosome 17p. Hum. Mol. Genet. 4, 1447–1452 (1995).

    Article  CAS  Google Scholar 

  11. Camuzat, A. et al. Evidence of genetic heterogeneity of Leber's congenital amaurosis (LCA) and mapping of LCA1 to chromosome 17p13. Hum. Genet. 97, 798–801 (1996).

    Article  CAS  Google Scholar 

  12. Murakami, A., Yajima, T. & Inana, G. Isolation of human retinal genes: recoverin cDNA and gene. Biochem. Biophys. Res. Commun. 187, 234–244 (1992).

    Article  CAS  Google Scholar 

  13. Calabrese, G. et al. Chromosome mapping of the human arrestin (SAG), β-arrestin 2 (ARRB2), and β-adrenergic receptor kinase 2 (ADRBK2) genes. Genomics 23, 286–288 (1994).

    Article  CAS  Google Scholar 

  14. Fitzgibbon, J. et al. Localization of thegeneencodinghuman phosphatidylinositol transfer protein (PITPN) to17p13.3:a gene showing homology to the Drosophilaretinal degeneration B gene (rdgB). Cyfogenet. Cell Genet. 67, 205–207 (1994).

    Article  CAS  Google Scholar 

  15. TombranTink, J., Pawar, H., Swaroop, A., Rodriguez, I. & Chader, G.J. Localization of the gene for pigment epithelium-derived factor (PEDF) to chromosome 17p13.1 and expression in cultured human retinoblastorna cells. Genomics 19, 266–272 (1994).

    Article  CAS  Google Scholar 

  16. Oliveira, L. et al. Human retinal guanylate cyclase (GUC2D) maps to chromosome 17p13.1 Genomics 22, 478–481 (1994).

    Article  CAS  Google Scholar 

  17. Yang, R.B., Fülle, H.J. & Garbers, D.L. Chromosomal localization and genomic organization of genes encoding guanylyl cyclase receptors expressed in olfactory sensory neurons and retina. Genomics 31, 367–372 (1996).

    Article  CAS  Google Scholar 

  18. Chabre, M. & Deterre, P. Molecular mechanism of visual transduction. Eur. J. Biochem. 179, 255–266 (1989).

    Article  CAS  Google Scholar 

  19. Dizhoor, A.M., Lowe, D.G., Olshevskaya, E.V., Laura, R.P. & Hurley, J.B. The human photoreceptor membrane guanylyl cyclase, ret GC, is present in outer segments and is regulated by calcium and a soluble activator. Neuron 12, 1345–1352 (1994).

    Article  CAS  Google Scholar 

  20. Lolley, R.N. & Lee, R.H. Cyclic GMP and photoreceptor function. FASEB. J. 4, 3001–3008 (1990).

    Article  CAS  Google Scholar 

  21. Yuen, P.S.T. & Garbers, D.L. Guanylyl cyclase-linked receptors. Annu. Rev. Neurosci. 15, 193–225 (1992).

    Article  CAS  Google Scholar 

  22. Garbers, D.L. & Lowe, D.G. Guanylyl cyclase receptors. J. Biol. Chem. 269, 30741–30744 (1994).

    CAS  PubMed  Google Scholar 

  23. Liu, X. et al. Ultrastructural localization of retinal guanylate cyclase in human and monkey retinas. Exp. Eye Res. 59, 761–768 (1994).

    Article  CAS  Google Scholar 

  24. Lee, N.R., Ulshafer, R.J. & Cohen, R.J. cGMP in the rd chicken retina. Invest. Ophthalmol. Vis. Sci. 28, 344 (1987).

    Google Scholar 

  25. Semple-Rowland, S.L., Buozylko, J., Palczewski, K. & Baehr, W. Abnormal expression of GCAP1 and photoreceptor guanylate cylcase rd chicken retina. Invest. Ophthalmol. Vis. Sci. 37 (suppl), 3729 (1996).

    Google Scholar 

  26. Rozet, J.M. et al. Structure and physical mapping of DR1, a TATA-binding protein associated phosphoprotein gene to chromosome 1 p22.1 and its exclusion in Stargardt's disease (STGD). Genomics (in the press).

  27. Shastry, B.A. Retinitis pigmentosa and related disorders: phenotypes of rhodopsin and petipherin/RDS mutations. Am. J. Med. Genet. 52, 467–474 (1994).

    Article  CAS  Google Scholar 

  28. McLaughlin, M.E., Sandberg, M.A., Berson, E.L. & Dryja, T.P. Recessive mutations in the gene encoding the βsubunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nature Genet. 4, 130–134 (1993).

    Article  CAS  Google Scholar 

  29. Huang, S.H. et al. Autosomal recessive retinitis pigmentosa caused by mutations in the α subunit of rod cGMP phosphodiesterase. Nature Genet. 11, 468 (1995).

    Article  CAS  Google Scholar 

  30. Dryja, T.P. et al. Mutations in the gene encoding the α subunit of the rod cGMPgated channel in autosomal recessive retinitis pigmentosa. Proc. Natl. Acad. Sci. USA 92, 10177–10181 (1995).

    Article  CAS  Google Scholar 

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Perrault, I., Rozet, J., Calvas, P. et al. Retinal–specific guanylate cyclase gene mutations in Leber's congenital amaurosis. Nat Genet 14, 461–464 (1996). https://doi.org/10.1038/ng1296-461

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