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An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness

Nature Genetics volume 19, pages 260–263 (1998)Cite this article

Abstract

The locus for the incomplete form of X-linked congenital stationary night blindness (CSNB2) maps to a 1.1-Mb region in Xp11.23 between markers DXS722 and DXS255. We identified a retina-specific calcium channel α1-subunit gene (CACNA1F) in this region, consisting of 48 exons encoding 1966 amino acids and showing high homology to L-type calcium channel α1–subunits. Mutation analysis in 13 families with CSNB2 revealed nine different mutations in 10 families, including three nonsense and one frameshift mutation. These data indicate that aberrations in a voltage-gated calcium channel, presumably causing a decrease in neurotransmitter release from photoreceptor presynaptic terminals, are a frequent cause of CSNB2.

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Figure 1: Physical mapping of CACNA1F.
Figure 2: CACNA1F encodes the α1-subunit of an L-type calcium channel.
Figure 3: Retinal specificity of CACNA1F.
Figure 4: RNA in situ hybridization.
Figure 5: Mutation analysis in family xlCSNB14.

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References

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

    Article  CAS  Google Scholar 

  2. 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 

  3. Miyake, Y., Horiuchi, M., Ota, I. & Shiroyama, N. Characteristic ERG flicker anomaly in incomplete congenital stationary night blindness. Invest. Ophthalmol. Vis. Sci. 28, 1816– 1823 (1987).

    CAS  Google Scholar 

  4. Lorenz, B., Andrassi, M. & Miliczek, K.D. Die inkomplette kongenitale stationäre Nachtblindheit (CSNB). Eine wichtige Differentialdiagnose des kongenitalen Nystagmus. Klin. Monatsbl. Augenheilkd. 208, 48– 55 (1996).

    Article  CAS  Google Scholar 

  5. Bergen, A.A.B., ten Brink, J.B., Riemslag, 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. Bech-Hansen, N.T. & Pearce, W.G. Manifestations of X-linked congenital stationary night blindness in three daughters of an affected male: Demonstration of homozygosity. Am. J. Hum. Genet. 52, 71–77 (1993).

    CAS  Google Scholar 

  7. 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 

  8. Hood, D.C. & Greenstein, V. Models of the normal and abnormal rod system. Vision Res. 30, 51– 68 (1990).

    Article  CAS  Google Scholar 

  9. Schmitz, Y. & Witkovsky, P. Dependence of photoreceptor glutamate release on a dihydropyridine-sensitive calcium channel. Neuroscience 78, 1209–1216 ( 1997).

    Article  CAS  Google Scholar 

  10. Hogan, K., Powers, P.A. & Gregg R.G. Cloning of the human skeletal muscle a subunit of the dihydropyridine-sensitive L-type calcium channel (CACNL1A3). Genomics 24, 608–609 (1994).

    Article  CAS  Google Scholar 

  11. Schultz, D. et al. Cloning, chromosomal localization, and functional expression of the α 1 subunit of the L-type voltage-dependent calcium channel from normal heart. Proc. Natl Acad. Sci. USA 90, 6228 –6232 (1990).

    Article  Google Scholar 

  12. Williams, M.E. et al. Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron 8, 71–84 (1992).

    Article  CAS  Google Scholar 

  13. Fisher, S.E. et al. Sequence-based exon prediction around the synaptophysin locus reveals a gene-rich area containing novel genes in human proximal Xp. Genomics 46, 340–347 (1997).

    Article  Google Scholar 

  14. Burge, C. & Karlin, S. Prediction of complete gene structures in human genomic DNA. J. Mol. Biol. 268, 78–94 (1997).

    Article  CAS  Google Scholar 

  15. Uberbacher, E.C. & Mural, R.J. Locating protein-coding regions in human DNA-sequences by a multiple sensor neural network approach. Proc. Natl Acad. Sci. USA 88, 11261– 11265 (1992).

    Article  Google Scholar 

  16. Stuhmer, W. et al. Structural parts involved in activation and inactivation of the sodium channel . Nature 339, 597–603 (1989).

    Article  CAS  Google Scholar 

  17. Schuster, A. et al. The IVS6 segment of the L-type calcium channel is critical for the action of dihydropyridines and phenylalkylamines. EMBO J. 15, 2365–2370 (1996).

    Article  CAS  Google Scholar 

  18. Sinnegger, M.J. et al. Nine L-type amino acid residues confer full 1,4-dihydropyridine sensitivity to the neuronal calcium channel alpha1A subunit. Role of L- type Met1188. J. Biol. Chem. 272, 27686–27693 (1997).

    Article  CAS  Google Scholar 

  19. Pragnell, M. et al. Calcium channel β-subunit binds to a conserved motif in the I-II cytoplasmic linker of the a1-subunit. Nature 368, 67–71 (1994).

    Article  CAS  Google Scholar 

  20. Witkovsky, P., Schmitz, Y., Akopian, A., Krizaj, D. & Tranchina, D. Gain of rod to horizontal cell synaptic transfer: relation to glutamate release and a dihydropyridine-sensitive calcium current. J. Neurosci. 17, 7297–7306 (1997).

    Article  CAS  Google Scholar 

  21. Stockton, M. & Slaughter, M.M. B-wave of the electroretinogram. A reflection of ON-bipolar cell activity. J. Gen. Physiol. 93, 101–122 (1989).

    Article  CAS  Google Scholar 

  22. Schindelhauer, D. et al. Long range map of a 3.5-Mb region in Xp11.23 with a sequence ready map from a 1.1 Mb gene-rich interval. Genome Res. 6, 1056–1069 (1996).

    Article  CAS  Google Scholar 

  23. Craxton, M. Cosmid sequencing . Methods Mol. Biol. 23, 149– 167 (1993).

    CAS  Google Scholar 

  24. Bonfield, J.K., Smith, K.F. & Staden, R. A new DNA sequence assembly program. Nucleic Acids Res. 24, 4992–4999 (1995).

    Article  Google Scholar 

  25. Leimeister, C., Bach, A. & Gessler, M. Developmental expression patterns of mouse sFRP genes encoding members of the secreted frizzled related protein family. Mech. Dev. (in press).

  26. Meindl, A. et al. A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). Nature Genet. 13, 35–42 ( 1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to the families who participated in this study. We thank B. Wissinger and M. Andrassi for sending DNA samples, K.B. Jedele for extensive help in manuscript preparation and H. Achatz for technical assistance. The work was supported by the German Federal Ministery for Education, Research and Technology by a grant to A.R. and A.M. as well as by Deutsche Retinitis Pigmentosa Gesellschaft by a grant to N.G.

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Authors and Affiliations

  1. Abteilung Medizinische Genetik der Ludwig-Maximilians-Universität, Goethestr. 29, München, 80336, Germany

    Tim M. Strom, Heide Hellebrand, Krisztina Wutz, Nadja Gutwillinger, Thomas Meitinger & Alfons Meindl

  2. Institut für Molekulare Biotechnologie, Am Beutenberg 11, Jena, 07745, Germany

    Gerald Nyakatura, Bernd Drescher & Andre Rosenthal

  3. Augenklinik der Universität, Tübingen, 72076, Germany

    Eckart Apfelstedt-Sylla, Klaus Rüther & Eberhart Zrenner

  4. Ophthalmogenetik der Augenklinik der Universität, Regensburg, 93042, Germany

    Birgit Lorenz

  5. Institut für Humangenetik, Am Hubland, Würzburg, 97074, Germany

    Bernhard H. F. Weber & Christian Sauer

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  1. Tim M. Strom
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Correspondence to Alfons Meindl.

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Strom, T., Nyakatura, G., Apfelstedt-Sylla, E. et al. An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nat Genet 19, 260–263 (1998). https://doi.org/10.1038/940

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