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The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein

Abstract

X-linked congenital stationary night blindness (XLCSNB) is characterized by impaired scotopic vision with associated ocular symptoms such as myopia, hyperopia, nystagmus and reduced visual acuity1. Genetic mapping in families with XLCSNB revealed two different loci on the proximal short arm of the X chromosome2. These two genetic subtypes can be distinguished on the basis of electroretinogram (ERG) responses and psychophysical testing as a complete (CSNB1) and an incomplete (CSNB2) form3,4. The CSNB1 locus has been mapped to a 5-cM linkage interval in Xp11.4 (refs 2,57). Here we construct and analyse a contig between the markers DXS993 and DXS228, leading to the identification of a new gene mutated in CSNB1 patients. It is partially deleted in 3 families and mutation analysis in a further 21 families detected another 13 different mutations. This gene, designated NYX, encodes a protein of 481 amino acids (nyctalopin) and is expressed at low levels in tissues including retina, brain, testis and muscle. The predicted polypeptide is a glycosylphosphatidylinositol (GPI)-anchored extracellular protein with 11 typical and 2 cysteine-rich, leucine-rich repeats (LRRs). This motif is important for protein-protein interactions and members of the LRR superfamily are involved in cell adhesion and axon guidance8,9,10. Future functional analysis of nyctalopin might therefore give insight into the fine-regulation of cell-cell contacts in the retina.

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Figure 1: Physical map of the 1.5-Mb CSNB1 region and position of NYX.
Figure 2: Mutations in NYX in CSNB1 families.
Figure 3: RT–PCR analysis of NYX expression.
Figure 4: Characterization of nyctalopin.

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References

  1. Heon, E. & Musarella, M.A. Congenital stationary night blindness: a critical review for molecular approaches. in Molecular Genetics Of Inherited Eye Disorders (eds Wright, A.F. & Jay, B.) 277–301 (Harwood Academic, Chur, Switzerland, 1994).

    Chapter  Google Scholar 

  2. Boycott, K.M. et al. Evidence for genetic heterogeneity in X-linked congenital stationary night blindness. Am. J. Hum. Genet. 62, 865–875 (1998).

    Article  CAS  Google Scholar 

  3. Miyake, Y., Yagasaki, K., Horiguchi, M., Kawase, Y. & Kanda, T. Congenital stationary night blindness with negative electroretinogram: a new classification. Arch. Ophthal. 104, 1013–1020 (1986).

    Article  CAS  Google Scholar 

  4. Ruether, K., Apfelstedt-Sylla, E. & Zrenner, E. Clinical findings in patients with congenital stationary night blindness of the Schubert-Bornschein type. Ger. J. Ophthalmol. 2, 429–435 (1993).

    CAS  Google Scholar 

  5. Bergen, A.A.B., ten Brink, J.B., Riemsiag, F., Schuurman, E.J.M. & Tijmes, N. Localization of a novel X-linked congenital stationary night blindness locus: close linkage to the RP3 type retinitis pigmentosa gene region. Hum. Mol. Genet. 4, 931–935 (1995).

    Article  CAS  Google Scholar 

  6. Rozzo, C. et al. Complete congenital stationary night blindness maps on Xp11.4 in a Sardinian family. Eur. J. Hum. Genet. 7, 574–578 (1999).

    Article  CAS  Google Scholar 

  7. Hardcastle, A.J., David-Gray, Z.K., Jay, M., Bird, A.C. & Bhattacharya, S.S. Localization of CSNBX (CSNB4) between the retinitis pigmentosa loci retinitis pigmentosa 2 and retinitis pigmentosa 3 on proximal Xp. Invest. Ophthalmol. Vis. Sci. 38, 2750–2755 (1997).

    CAS  Google Scholar 

  8. Kobe, B. & Deisenhofer, J. The leucine-rich repeat: a versatile binding motif. Trends Biol. Sci. 19, 415–421 (1994).

    Article  CAS  Google Scholar 

  9. Krantz, D.E. & Zipursky, S.L. Drosophila chaoptin, a member of the leucine-rich repeat family, is a photoreceptor cell-specific adhesion molecule. EMBO J. 6, 1969–1977.

  10. Nose, A., Takeichi, M. & Goodman, C.S. Ectopic expression of connectin reveals a repulsive function during growth cone guidance and synapse formation. Neuron 13, 525–539 (1994).

    Article  CAS  Google Scholar 

  11. Schubert, G. & Bornschein, H. Beitrag zur Analyse des menschlichen Electroretinogramm. Ophthalmologica 123, 396–413 (1952).

    Article  CAS  Google Scholar 

  12. Strom, T. et al. An L-type calcium channel gene is mutated in incomplete X-linked congenital stationary night blindness. Nature Genet. 19, 260–263 (1998).

    Article  CAS  Google Scholar 

  13. Bech-Hansen, N.T. et al. Loss-of-function mutations in a calcium-channel α1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness. Nature Genet. 19, 264–267 (1998).

    Article  CAS  Google Scholar 

  14. Ollendorff, V., Noguchi, T., deLapreyiere, O. & Birnbaum, D. The GARP gene encodes a new member of the family of leucine-rich repeat-containing proteins. Cell Growth Differ. 5, 213–219 (1994).

    CAS  Google Scholar 

  15. Bech-Hansen, N.T. et al. Mutations in a gene encoding a new leucine-rich protein, nyctalopin, cause X-linked complete congenital stationary night blindness. Nature Genet. 26, 319–323 (2000).

    Article  CAS  Google Scholar 

  16. Phelan, J.K. & Bok, D. Analysis and quantitation of mRNAs encoding the α- and β-subunits of rod photoreceptor cGMP phosphodiesterase in neonatal retinal degeneration (rd) mouse retinas. Exp. Eye Res. 71, 119–128 (2000).

    Article  CAS  Google Scholar 

  17. Iozzo, R.V. The family of the small leucine-rich proteoglycans: key regulators of matrix assembly and cellular growth. Crit. Rev. Biochem. Mol. Biol. 32, 141–174 (1997).

    Article  CAS  Google Scholar 

  18. Leong, S.R., Baxter, R.C., Camerato, T., Dai, J. & Wood, W.I. Structure and functional expression of the acid-labile subunit of the insulin-like growth factor binding complex. Mol. Endocrinol. 6, 860–876 (1992).

    Google Scholar 

  19. Hickey, M.J., Hagen, F.S., Yagi, M. & Roth, G.J. Human platelet glycoprotein V: characterization of the polypeptide and the related Ib-V-IX receptor system of adhesive, leucine-rich glycoproteins. Proc. Natl Acad. Sci. USA 90, 8237–8331 (1993).

    Article  Google Scholar 

  20. Rothberg, J.M., Hartley, D.A., Walther, Z. & Artavanis-Tsakonas, S. Slit: an EGF-homologous locus of D. melanogaster involved in the development of the embryonic central nervous system. Cell 55, 1047–1059 (1988).

    Article  CAS  Google Scholar 

  21. Janosi, J.B. et al. The acid-labile subunit of the serum insulin-like growth factor-binding protein complexes: structural determination by molecular modeling and electron microscopy. J. Biol. Chem. 274, 23328–23332 (1999).

    Article  CAS  Google Scholar 

  22. Guex, N. & Peitsch, M.C. Swiss-Model and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18, 2714–2723 (1997).

    Article  CAS  Google Scholar 

  23. Peitsch, M.C. ProMod and Swiss-Model: Internet-based tools for automated comparative protein modeling. Biochem. Soc. Trans. 24, 274–279 (1996).

    Article  CAS  Google Scholar 

  24. Peitsch, M.C. Protein modeling by E-mail. Biotechnology 13, 658–660 (1995).

    CAS  Google Scholar 

  25. Hobby, P. et al. Cloning, modeling, and chromosomal localization for a small leucine-rich repeat proteoglycan (SLRP) family member expressed in human eye. Mol. Vis. 6, 72–78 (2000).

    CAS  Google Scholar 

  26. Pardue, M.T., McCall, M., LaVail, M., Gregg, R.G. & Peachey, N.S. A naturally occuring mouse model of X-linked congenital stationary night blindness. Invest. Ophthalmol. Vis. Sci. 39, 2443–2449 (1998).

    CAS  Google Scholar 

  27. Bernstein, S.L., Borst, D.E., Neuder, M.E. & Wong, P. Characterization of a human fovea cDNA library and regional differential gene expression in the retina. Genomics 32, 301–308 (1996).

    Article  CAS  Google Scholar 

  28. Roepman, R. et al. Identification of a gene disrupted by a microdeletion in a patient with X-linked retinitis pigmentosa (XLRP). Hum. Mol. Genet. 5, 827–833 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the patients and family members for participation; J. Ramser for genomic database screening; and A. Bird, A. Blankenagel, E. Apfelstedt-Sylla, K. Ruether, T Rosenberg and F.P.M. Cremers for patient samples. This work was supported by the German Ministery for Research and Education (A.M.), the Deutsche Forschungsgemeinschaft (W.B.), the Foundation Fighting Blindness (A.M., W.B.) and Interdisziplinäres Zentrum für Klinische Forschung at the University of Tübingen (B.W.).

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Correspondence to Alfons Meindl.

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Department of Experimental Pathology, Lund University, Lund, Sweden

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Pusch, C., Zeitz, C., Brandau, O. et al. The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein. Nat Genet 26, 324–327 (2000). https://doi.org/10.1038/81627

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