Summary
A candidate gene for Norrie disease, a rare X-linked eye disorder (McKusick no.310600) frequently accompanied by deafness and mental disturbances, has been isolated by positional cloning. The locus for Norrie disease has been assigned to Xp11.3 through both linkage analysis and deletion mapping. The DXS7 locus and both the monoamine oxidase genes were found to be linked to the disease locus. By subcloning a YAC clone encompassing these loci and overlapping the most proximal breakpoint in Norrie deletion patients, evolutionary conserved cDNA’s were isolated from retinal as well as brain cDNA libraries. One isolated cDNA has a length of 1.9 kb, contains an open reading frame of 399 bp which codes for a 133 amino acids long peptide and is disrupted in two Norrie patients with intragenic deletions.
The gene consists of three exons spanning over 27 kb with the first exon untranslated. Sequencing all three exons from different Norrie patients revealed missense and nonsense mutations as well as one splice-site mutation. Neither null alleles nor specific mutations can be correlated to a specific Norrie phenotype even in a single family suggesting a strong influence of genetic background. The major part of the Norrie protein contains a cysteine rich domain and by focussing the homology search on the number and the spacing of cysteine residues, we have detected similarities between the predicted product of the Norrie gene and a carboxyl-terminal domain which is common to a group of proteins including extracellular mucins. Missense mutations replacing evolutionary conserved cysteine residues emphasize the functional importance of these sites. Striking similarities to extracellular factors as well as histopathological findings point to a possible role of the Norrie gene product in retinal cell-cell interactions.
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References
Norrie, G. Causes of blindness in children. Acta Ophthalmol. 5:357–386 (1927)
Warburg, M. Norrie’s disease: A new hereditary bilateral pseudotumor of the retina. Acta Ophtalmol. 39, 757–772 (1961)
Warburg, M. Norrie’s disease: A congenital progressive oculo-acoustico-cerebral degeneration. Acta Ophtalmol. (Suppl. 89) 1–147 (1966)
Zergollem, L. and Cupak, K. Norrie-Warburg syndrome. Acta med.iug. 40:263–273 (1986)
Donnai, D., Mountford, R.C. and Read, A.P. Norrie disease resulting from a gene deletion clinical features and DNA studies. J. Med. Genet. 25:73–78 (1988)
Moreira-Filho, C.A., Neustein,1. A presumtive new variant of Norrie disease. J. Med. Genet. 16:125–128 (1979)
Gal, A., Wieringa, B., Smeets, D.F.C.M., Bleeker-Wagemakers, L.M. and Ropers, H.-H. Submicroscopic interstitial deletion of the X-chromosome explains a complex genetic syndrome dominated by Norrie disease. Cytogenet. Cell. Genet. 42:219–224 (1986)
Townes, P.L. and Roca, P.D. Norrie’s disease (hereditary oculo-acoustico-cerebral degeneration). Am.J. Ophthalmol. 76:797–803 (1973)
Gal, A., Stolzenberger C., Wienker, T.F., et al. Norrie’s disease: close linkage with genetic markers from the proximal short arm of the X chromosome. Clin. Genet. 27:282–283 (1985)
Bleeker-Wagemakers, L.M., Friedrich, U., Wienker, T.F., Warburg, M. and Ropers, H.H. Close linkage between Norrie disease, a cloned DNA sequence from the proximal short arm and the centromere of the X chromosome. Hum. Genet. 71:211–214 (1985)
Sims, K.B., Lebo, R.V., Benson, G. et al. The Norrie disease maps to a 150 kb region on chromosome Xp11.3. Hum. molec. Genet. 1:83–89 (1992)
De la Chapelle, A., Sankila, E.-M., Lindlöf, M., Aula, P. and Norio, R. Norrie disease caused by a gene deletion allowing carrier detection and prenatal diagnosis. Clin. Genet. 28:317–320 (1985)
Berger, W., Meindl, A., van de Pol, T.J.R. et al. Isolation of a candidate gene for Norrie disease by positional cloning. Nature Genetics 1:199–203 (1992)
Chen, Z.-Y., Hendriks R.W., Jobling, M.A. et al. Isolation and characterization of a candidate gene for Nome disease Nature Genetics 1:204–208 (1992)
Breathnach, R. and Chambon, P. Organization and expression of eucaryotic split genes coding for proteins Ann. Rev. Biochem. 50:349–383 (1981)
Rupp, R.A.W. and Sippel, A.E. Chicken liver TGGCA protein purified by preparative mobility shift electrophoresis shows a 36.8 to 29.8 kd microheterogeneity. Nucl. Acids Res. 15:9707–9726 (1987)
Sims, K.B., Schuback, D., Solc, C.K. et al. The Norrie disease gene: predictions about the encoded proteinnorrin, and RNA expression studies. Am. J. Hum. Genet. 51:A43 abstract
Berger, W., van de Pol, D., Warburg, M., et al. Mutation in the candidate gene for Norrie disease. Hum. molec. Genet. 7:461–465 (1992)
Meindl, A., Berger, W., Meitinger, T. et al. Norrie disease is caused by mutations in an extracellular protein resembling C-terminal globular domains of mucins. Nature Genetics 2:139–143 (1992)
Kyte, J. and Doolittle, R.F. A simple method for displaying the hydropathic character of a protein J. Mol. Biol. 157:105–132 (1986)
Pearson, W.R. and Lipman, D.J. Improved tools for biological sequence comparison. Proc. Natl. Acad. Sci. USA 85:2444–2448 (1988)
Eckhardt, A.E., Timpte, C.S., Abernethy, J.L., Zhao, Y. and Hill, R.L. Porcine sub-maxillary mucin contains a cysteine-rich, carboxyl-terminal domain in addition to a highly repetitive, glycosylated domain. J. Biochemistry 266:9678–9686 (1991)
Probst, J.C., Gertzen, E.M. and Hoffmann, W. An integumentary mucin (FIM-B.1) from Xenopus laevis homologous with von Willebrand factor Biochemistry 29:6240–6244 (1990)
Bhargava, A.K., Woitach, J.T., Davidson and Bhavanadan, V.P. Cloning and cDNA sequence of a bovine submaxillary gland mucin-like protein containing two distinct domains. Proc. Natl. Acad. Sci. USA 87:6798–6802 (1990)
Slit: an extracellular protein necessary for development of midline glia and commisural axon pathways contains both EGF and LRR domains. Genes and Development 4:2169–2187 (1990)
Titani, K. et al. Amino acid sequence of human von Willebrand factor.Biochemistry 25:3171–3184 (1986)
Structure of pre-pro-von Willebrand factor and its expression in heterologous cells.Nature 324:270–273 (1986)
Simmons, D.L., Levy, D.B. Yannoni, Y. and Eriksson, R.L. Identification of a phorbol ester-repressible v-src inducible gene. Proc. Natl. Acad. Sci. USA 86:1178–1182 (1989)
O’Brien, T.P., Yang, G.P., Sanders, L. and Lau, L.F. Expression of cyr61, a growth factor-inducible immediate-early gene. Mol. and Cell. Biol. 10:3569–3577 (1990)
Higgins, D.G. and Sharp, P.M. CLUSTAL a package for performing multiple sequence alignment on a microcomputer Gene 73:237–244 (1988)
Parsons, M.A., Curtis, D., Blank, C.E., Hughes H.N., McCartney A.C.E., The ocular pathology of Nome disease in a fetus of 11 weeks. Graefe’s Arch. Exp. Ophthalmol. 230:248–251 (1992)
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Meitinger, T., Meindl, A., Berger, W., Ropers, HH. (1993). The Norrie Disease Gene: Positional Cloning, Mutation Analysis and Protein Homologies. In: Hollyfield, J.G., Anderson, R.E., LaVail, M.M. (eds) Retinal Degeneration. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2974-3_13
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DOI: https://doi.org/10.1007/978-1-4615-2974-3_13
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