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Gene Review

NDP  -  Norrie disease (pseudoglioma)

Homo sapiens

Synonyms: EVR2, FEVR, ND, Norrie disease protein, Norrin, ...
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Disease relevance of NDP

  • Loss of function of the NDP gene causes a syndrome of congenital blindness and progressive hearing loss, sometimes accompanied by signs of CNS dysfunction, including variable mental retardation and psychiatric symptoms [1].
  • A series of subclones prepared from a 'phage library (lambda DASH II) of the YAC have been characterised and have been employed to determine the end point of the deletion of a Norrie disease (NDP) patient who has been shown to lack both DXS7 and MAO coding sequences [2].
  • Coats' disease of the retina (unilateral retinal telangiectasis) caused by somatic mutation in the NDP gene: a role for norrin in retinal angiogenesis [3].
  • The finding of a mutation in NDP in association with peripheral vascular disease may provide valuable insight into the potential role of this gene in cellular processes [4].
  • However, venous insufficiency is a clinical finding not reportedly associated with Norrie disease [4].

Psychiatry related information on NDP


High impact information on NDP

  • Loci associated with FEVR map to 11q13-q23 (EVR1; OMIM 133780, ref. 1), Xp11.4 (EVR2; OMIM 305390, ref. 2) and 11p13-12 (EVR3; OMIM 605750, ref. 3). Here we have confirmed linkage to the 11q13-23 locus for autosomal dominant FEVR in one large multigenerational family and refined the disease locus to a genomic region spanning 1.55 Mb [10].
  • The observations suggest that phenotypes of both XLFEVR and Norrie disease can result from mutations in the same gene [11].
  • Our model identifies NDP as a member of an emerging family of growth factors containing a cystine knot motif, with direct implications for the physiological role of NDP [12].
  • The X-lined gene for Norrie disease, which is characterized by blindness, deafness and mental retardation has been cloned recently [12].
  • Sequence pattern searches and three-dimensional modelling now suggest that the Norrie disease protein (NDP) has a tertiary structure similar to that of transforming growth factor beta (TGF beta) [12].

Chemical compound and disease context of NDP

  • We have followed the dynamic evolution of intracellular pH and of the intracellular concentration of nucleotides (NDP, NTP), Pi and lactate in maize root tips during the course of normoxia and anoxia transition [13].
  • Nucleoside diphosphate kinases (NDP kinases), products of the nm23 gene, catalyze the transfer of the terminal phosphate group of the nucleoside triphosphate to the corresponding diphosphate and may be involved in tumor metastasis suppression, development, and signal transduction [14].
  • From January 2000 to December 2004, a total of 12 esophageal cancer patients with locally advanced and metastatic esophageal cancer (stages II-IVB) were treated with radiation therapy (50.4 Gy) combined with nedaplatin (80 mg/m(2), bolus infusion) and 5-FU (800 mg/m(2)/24 h, continuous infusion for 4 days) (NDP group) [15].

Biological context of NDP

  • To date three loci have been mapped: EVR1 on chromosome 11q, EVR2 on chromosome Xp, and EVR3 on chromosome 11p [16].
  • Issues that remain to be resolved are the function of the NDP gene product, the frequency and phenotype of the MAOA deficiency state, and the possible occurrence and phenotype of an MAOB deficiency state [1].
  • Computer analysis and experimental data have resulted in the identification of several putative loci, including a phosphatase inhibitor 2-like gene (dJ154.1) and a 250-bp sequence which resembles a homeobox domain (dA113.3), 1.2 Mb and 400 kb respectively from the MAO/NDP cluster [17].
  • The Norrie disease and MAO genes are tandemly arranged in the p11.4-p11.3 region of the human X chromosome in the order tel-MAOA-MAOB-NDP-cent [1].
  • Norrie disease (ND), atrophia bulborum hereditaria, is caused by a gene defect on the proximal short arm of the X-chromosome [18].

Anatomical context of NDP

  • Screening of cDNA libraries has enabled us to isolate and sequence a likely candidate gene for Norrie disease which is expressed in retina, choroid and fetal brain [19].
  • Replacement of valine at residue 60 in norrin by glutamic acid, a mutation found in humans with a severe type of Norrie disease, results in a considerable reduction (50%) in the amount of norrin in the extracellular matrix of transfected COS-7 cells [20].
  • Using somatic cell hybrids, in situ hybridization, and field-inversion gel electrophoresis as well as deletion mapping in a patient with Norrie disease, we concluded that these two genes are close to each other and to the DXS7 locus (Xp 11.3) [21].
  • Because the OATL1 ScaI RFLP is a relatively common polymorphism, this system should be useful for the identification of ND carriers and affected male fetuses and newborns [22].
  • Genomic DNA was isolated from the peripheral blood leukocytes of these patients, and all three exons and their flanking areas, all known ND gene mutations regions, were evaluated following amplification by a polymerase chain reaction, but no ND gene mutations were detected [23].

Associations of NDP with chemical compounds

  • The MAO genes appear to have arisen by tandem duplication of an ancestral MAO gene, but their positional relationship to NDP appears to be random [1].
  • RESULTS: Two molecular defects found in the NDP gene were: a missense mutation (265C > G) within codon 97 that resulted in the interchange of arginine by proline, and a partial deletion in the untranslated 3' region of exon 3 of the NDP gene [24].
  • Replacement of arginine at residue 121 by glutamine, which is associated with a less severe type of Norrie disease, results in a reduction in the amount of norrin R121Q in the extracellular matrix (26%) [20].
  • A candidate gene approach using the Norrie disease gene (NDP), which maps to Xp11.3, revealed a point mutation in the third exon resulting in substitution of phenylalanine for leucine at position 61 [4].
  • The mutation at codon 128 occurs at the 10th cysteine and might be expected to alter the function of the ND protein [25].

Physical interactions of NDP

  • The C-terminal segment (Gly10-Lys11-Pro12-Val13) of NDP was clearly important for binding to all the four melanocortin receptor subtypes [26].

Enzymatic interactions of NDP


Regulatory relationships of NDP


Other interactions of NDP

  • Distinctive X-linked syndromes have been described for mutations in the MAOA and NDP genes, and in addition, individuals have been identified with contiguous gene syndromes due to chromosomal deletions which encompass two or three of these genes [1].
  • Molecular hybridization experiments with 19 cloned DNA fragments have enabled us to construct a preliminary long-range restriction map around DXS77, DXS7, MAO-A and MAO-B, and to localize the distal end point of an ND deletion between DXS77 and DXS7 [18].
  • X-linked recessive primary retinal dysplasia is linked to the Norrie disease locus [29].
  • BACKGROUND/AIMS: Familial exudative vitreoretinopathy (FEVR) is associated with mutations in the Norrie disease gene in X linked pedigrees and with linkage to the EVR1 locus at 11q13 in autosomal dominant cases [30].
  • Seven polymerase chain reaction primer pairs spanning the NDP were optimized for denaturing high performance liquid chromatography and direct sequencing [31].

Analytical, diagnostic and therapeutic context of NDP


  1. Norrie disease and MAO genes: nearest neighbors. Chen, Z.Y., Denney, R.M., Breakefield, X.O. Hum. Mol. Genet. (1995) [Pubmed]
  2. Characterization of a YAC containing part or all of the Norrie disease locus. Chen, Z.Y., Sims, K.B., Coleman, M., Donnai, D., Monaco, A., Breakefield, X.O., Davies, K.E., Craig, I.W. Hum. Mol. Genet. (1992) [Pubmed]
  3. Coats' disease of the retina (unilateral retinal telangiectasis) caused by somatic mutation in the NDP gene: a role for norrin in retinal angiogenesis. Black, G.C., Perveen, R., Bonshek, R., Cahill, M., Clayton-Smith, J., Lloyd, I.C., McLeod, D. Hum. Mol. Genet. (1999) [Pubmed]
  4. Norrie disease gene mutation in a large Costa Rican kindred with a novel phenotype including venous insufficiency. Rehm, H.L., Gutiérrez-Espeleta, G.A., Garcia, R., Jiménez, G., Khetarpal, U., Priest, J.M., Sims, K.B., Keats, B.J., Morton, C.C. Hum. Mutat. (1997) [Pubmed]
  5. Cataplexy and monoamine oxidase deficiency in Norrie disease. Vossler, D.G., Wyler, A.R., Wilkus, R.J., Gardner-Walker, G., Vlcek, B.W. Neurology (1996) [Pubmed]
  6. Broad therapeutic treatment window of [Nle(4), D-Phe(7)]alpha-melanocyte-stimulating hormone for long-lasting protection against ischemic stroke, in Mongolian gerbils. Giuliani, D., Leone, S., Mioni, C., Bazzani, C., Zaffe, D., Botticelli, A.R., Altavilla, D., Galantucci, M., Minutoli, L., Bitto, A., Squadrito, F., Guarini, S. Eur. J. Pharmacol. (2006) [Pubmed]
  7. Analysis of the monoamine oxidase genes and the Norrie disease gene locus in narcolepsy. Koch, H., Craig, I., Dahlitz, M., Denney, R., Parkes, D. Lancet (1999) [Pubmed]
  8. Genetic factors in human sleep disorders with special reference to Norrie disease, Prader-Willi syndrome and Moebius syndrome. Parkes, J.D. Journal of sleep research. (1999) [Pubmed]
  9. DNA techniques in prenatal diagnosis and in genetic pathology. Rehder, H., Friedrich, U. American journal of medical genetics. Supplement. (1987) [Pubmed]
  10. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Robitaille, J., MacDonald, M.L., Kaykas, A., Sheldahl, L.C., Zeisler, J., Dubé, M.P., Zhang, L.H., Singaraja, R.R., Guernsey, D.L., Zheng, B., Siebert, L.F., Hoskin-Mott, A., Trese, M.T., Pimstone, S.N., Shastry, B.S., Moon, R.T., Hayden, M.R., Goldberg, Y.P., Samuels, M.E. Nat. Genet. (2002) [Pubmed]
  11. A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Chen, Z.Y., Battinelli, E.M., Fielder, A., Bundey, S., Sims, K., Breakefield, X.O., Craig, I.W. Nat. Genet. (1993) [Pubmed]
  12. Molecular modelling of the Norrie disease protein predicts a cystine knot growth factor tertiary structure. Meitinger, T., Meindl, A., Bork, P., Rost, B., Sander, C., Haasemann, M., Murken, J. Nat. Genet. (1993) [Pubmed]
  13. Kinetic studies of the variations of cytoplasmic pH, nucleotide triphosphates (31P-NMR) and lactate during normoxic and anoxic transitions in maize root tips. Saint-Ges, V., Roby, C., Bligny, R., Pradet, A., Douce, R. Eur. J. Biochem. (1991) [Pubmed]
  14. Rapid purification and characterization of nucleoside diphosphate kinase isoforms using ATP-sepharose affinity column chromatography. Kim, S.Y., Chang, K.H., Doh, H.J., Jung, J.A., Kim, E., Sim, C.J., Lee, K.J. Mol. Cells (1997) [Pubmed]
  15. Radiation therapy combined with cis-diammine-glycolatoplatinum (nedaplatin) and 5-fluorouracil for Japanese stage II-IV esophageal cancer compared with cisplatin plus 5-fluorouracil regimen: a retrospective study. Yamashita, H., Nakagawa, K., Tago, M., Igaki, H., Nakamura, N., Shiraishi, K., Sasano, N., Ohtomo, K. Dis. Esophagus (2006) [Pubmed]
  16. Identification of a fourth locus (EVR4) for familial exudative vitreoretinopathy (FEVR). Toomes, C., Downey, L.M., Bottomley, H.M., Scott, S., Woodruff, G., Trembath, R.C., Inglehearn, C.F. Mol. Vis. (2004) [Pubmed]
  17. Sequence analysis and transcript identification within 1.5 MB of DNA deleted together with the NDP and MAO genes in atypical Norrie disease patients presenting with a profound phenotype. Suárez-Merino, B., Bye, J., McDowall, J., Ross, M., Craig, I.W. Hum. Mutat. (2001) [Pubmed]
  18. Physical fine-mapping of a deletion spanning the Norrie gene. Diergaarde, P.J., Wieringa, B., Bleeker-Wagemakers, E.M., Sims, K.B., Breakefield, X.O., Ropers, H.H. Hum. Genet. (1989) [Pubmed]
  19. Isolation of a candidate gene for Norrie disease by positional cloning. Berger, W., Meindl, A., van de Pol, T.J., Cremers, F.P., Ropers, H.H., Döerner, C., Monaco, A., Bergen, A.A., Lebo, R., Warburg, M. Nat. Genet. (1992) [Pubmed]
  20. Norrie disease protein (norrin) forms disulfide-linked oligomers associated with the extracellular matrix. Perez-Vilar, J., Hill, R.L. J. Biol. Chem. (1997) [Pubmed]
  21. Human monoamine oxidase A and B genes map to Xp 11.23 and are deleted in a patient with Norrie disease. Lan, N.C., Heinzmann, C., Gal, A., Klisak, I., Orth, U., Lai, E., Grimsby, J., Sparkes, R.S., Mohandas, T., Shih, J.C. Genomics (1989) [Pubmed]
  22. Linkage analysis of Norrie disease with an X-chromosomal ornithine aminotransferase locus. Bateman, J.B., Kojis, T.L., Cantor, R.M., Heinzmann, C., Ngo, J.T., Spence, M.A., Inana, G., Kivlin, J.D., Curtis, D., Sparkes, R.S. Transactions of the American Ophthalmological Society. (1993) [Pubmed]
  23. Mutations of the Norrie gene in Korean ROP infants. Kim, J.H., Yu, Y.S., Kim, J., Park, S.S. Korean journal of ophthalmology : KJO. (2002) [Pubmed]
  24. Molecular analysis of the NDP gene in two families with Norrie disease. Rivera-Vega, M.R., Chiñas-Lopez, S., Vaca, A.L., Arenas-Sordo, M.L., Kofman-Alfaro, S., Messina-Baas, O., Cuevas-Covarrubias, S.A. Acta ophthalmologica Scandinavica. (2005) [Pubmed]
  25. Identification of a nonsense mutation at codon 128 of the Norrie's disease gene in a male infant. Wong, F., Goldberg, M.F., Hao, Y. Arch. Ophthalmol. (1993) [Pubmed]
  26. Selective properties of C- and N-terminals and core residues of the melanocyte-stimulating hormone on binding to the human melanocortin receptor subtypes. Schiöth, H.B., Mutulis, F., Muceniece, R., Prusis, P., Wikberg, J.E. Eur. J. Pharmacol. (1998) [Pubmed]
  27. Characterization of cell lines stably expressing human normal or mutated EGFP-tagged MC4R. Blondet, A., Doghman, M., Rached, M., Durand, P., Bégeot, M., Naville, D. J. Biochem. (2004) [Pubmed]
  28. Change in gene expression profile induced by alpha-melanocyte stimulating hormone in a malignant mesothelioma cell line. Colombo, G., Sordi, A., Turcatti, F., Carlin, A., Rossi, C., Lonati, C., Santambrogio, L., Gatti, S., Catania, A. Cell. Mol. Biol. (Noisy-le-grand) (2006) [Pubmed]
  29. X-linked recessive primary retinal dysplasia is linked to the Norrie disease locus. Ravia, Y., Braier-Goldstein, O., Bat-Miriam, K.M., Erlich, S., Barkai, G., Goldman, B. Hum. Mol. Genet. (1993) [Pubmed]
  30. Genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of the EVR1 locus on chromosome 11q in a large autosomal dominant pedigree. Bamashmus, M.A., Downey, L.M., Inglehearn, C.F., Gupta, S.R., Mansfield, D.C. The British journal of ophthalmology. (2000) [Pubmed]
  31. Norrie disease gene sequence variants in an ethnically diverse population with retinopathy of prematurity. Hutcheson, K.A., Paluru, P.C., Bernstein, S.L., Koh, J., Rappaport, E.F., Leach, R.A., Young, T.L. Mol. Vis. (2005) [Pubmed]
  32. Clinical reinvestigation and linkage analysis in the family with Episkopi blindness (Norrie disease). Wolff, G., Mayerová, A., Wienker, T.F., Atalianis, P., Ioannou, P., Warburg, M. J. Med. Genet. (1992) [Pubmed]
  33. Ocular findings associated with a Cys39Arg mutation in the Norrie disease gene. Joos, K.M., Kimura, A.E., Vandenburgh, K., Bartley, J.A., Stone, E.M. Arch. Ophthalmol. (1994) [Pubmed]
  34. Detection of a new submicroscopic Norrie disease deletion interval with a novel DNA probe isolated by differential Alu PCR fingerprint cloning. Bergen, A.A., Wapenaar, M.C., Schuurman, E.J., Diergaarde, P.J., Lerach, H., Monaco, A.P., Bakker, E., Bleeker-Wagemakers, E.M., van Ommen, G.J. Cytogenet. Cell Genet. (1993) [Pubmed]
  35. A C597-->A polymorphism in the Norrie disease gene is associated with advanced retinopathy of prematurity in premature Kuwaiti infants. Haider, M.Z., Devarajan, L.V., Al-Essa, M., Kumar, H. J. Biomed. Sci. (2002) [Pubmed]
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