Advertisement

Mutations in the Gene for the B-Subunit of Rod Photoreceptor Cgmp-Specific Phosphodiesterase (PDEB) in Patients with Retinal Dystrophies and Dysfunctions

  • A. Veske
  • U. Orth
  • K. Rüther
  • E. Zrenner
  • T. Rosenberg
  • W. Baehr
  • A. Gal

Summary

Rod photoreceptor cGMP-specific phosphodiesterase (PDE) is a key enzyme of the phototransduction cascade. Mutations in the gene encoding the β-subunit of PDE (βPDE) have been implicated in two distinct human retinal disorders; autosomal recessive retinitis pigmentosa (arRP) and autosomal dominant congenital stationary night blindness (adCSNB).

We examined the βPDE gene in 101 unrelated patients with arRP from Germany for sequence changes by single strand conformation polymorphism analysis. Band shifts were detected in 17 different gene fragments amplified by polymerase chain reaction. Direct sequencing revealed 11 single base substitutions that were considered being most likely polymorphisms. Of the remaining six, and most likely disease related exonic mutations, three (225C→T/Arg74Cys, 226insC, and 660T→C/Tyr219His) have been found in patients with only one (heterozygous) βPDE-mutation identified so far. In two patients, both βPDE-alleles carried potentially pathogenic mutations; one patient was homozygote for the 1585T→C/Leu527Pro change while the other one was a compound hetrrozygote for 897C→T/Gln298stop and 2565C→G/Leu854Val. This latter patient, a 19-year-old female, presented with typical clinical, electrophysiological, and psychophysical symptoms of a rod-cone degeneration.

We have recently described a large multigeneration Danish pedigree with adCSNB, in which the photoreceptor dysfunction was cosegregating with a heterozygous His258Asn mutation of the βPDE gene. Here we report two further Danish pedigrees with adCSNB and the His258Asn mutation. Both families were shown to be unrelated to the original pedigree for (at least the last) 6 generations. Nevertheless, genotyping for 11 different intragenic DNA polymorphisms revealed that night blind subjects in the three families shared the same βPDE haplotype suggesting that the His258Asn allele originated from a common ancestor. Assuming that the three families were linked in the seventh generation, a maximum lod score of 28.615 at theta = 0.00 was obtained for the linkage relationship between the loci for adCSNB and βPDE. These data provide strong support for the hypothesis that the mutant βPDE is responsible for CSNB in this family, i.e. that the molecular defect is in the phototransduction cascade and at the photoreceptor level.

Keywords

Retinitis Pigmentosa Night Blindness Retinal Dystrophy Single Strand Conformation Polymorphism Analysis Heterozygous Missense Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Pfister, C., Bennett, N., Bruckert, F., Catty, P., Clerc, A., Pages, F., and Deterre, P., 1993, Interactions of a G-protein with its effector: transducin and cGMP phosphodiesterase in retinal rods, Cell. Signalling 5:235–251.PubMedCrossRefGoogle Scholar
  2. 2.
    Weber, B., Riess, O., Hutchinson, G., Collins, C., Lin, B., Kowbel, D., Andrew, S., Schappert, K., and Hayden, M.R., 1991, Genomic organization and complete sequence of the human gene encoding the ß-subunit of the cGMP phosphodiesterase and its localisation to 4p 16.3, Nucleic Acids Res. 19:6263–6268.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Gal, A., Orth, U., Baehr, W., Schwinger, E., and Rosenberg, T, 1994, Heterozygous missense mutation in the rod cGMP phosphodiesterase β-subunit gene in autosomal dominant stationary night blindness, Nature Genet. 7:64–68.PubMedCrossRefGoogle Scholar
  4. 4.
    Haim, M., Holm, N.V. and Rosenberg, T., 1992, Prevalence of retinitis pigmentosa and allied disorders in Denmark. I. Main results, Acta Ophthalmol. (Copenh) 70:178–186.CrossRefGoogle Scholar
  5. 5.
    Boughman, J.A., Conneally, P.M., and Nance, W.E., 1980, Population genetic studies of retinitis pigmentosa, Am. J. Hum. Genet. 32:223–235.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Humphries, P., Kenna, P., and Farrar J.G., 1992, On the molecular genetics of retinitis pigmentosa, Science 256:804–808.PubMedCrossRefGoogle Scholar
  7. 7.
    Leutelt, J., Oehlman, R., Younus, F., van den Born, I., Weber, J.L., Denton, M.J., Mehdi, Q.S., and Gal, A., 1995, Autosomal recessive retinitis pigmentosa locus maps on chromosome 1 q in a large consanguineous family from Pakistan, Clin. Genet, (in press)Google Scholar
  8. 8.
    van Soest, S., van den Bora, I.L., Gal, A., Farrar, J.G., Bleeker-Wagemakers, L.M., Westerveld, A., Humphries, P., Sandkuijl, L.A., and Bergen, A.A., 1994, Assignment of a gene for autosomal recessive retinitis pigmentosa (RP12) to chromosome 1q31-q32.1 in an inbred and genetically heterogeneous disease population, Genomics 22:499–504.PubMedCrossRefGoogle Scholar
  9. 9.
    Knowles, J.A., Shugart, L., Banerjee, P., Gilliam, T.C., Lewis, C.A., Jacobson, S.G., and Ott, J., 1994, Identification of a locus, distinct from RDS-peripherin, for autosomal recessive retinitis pigmentosa on chromosome 6p, Hum. Mol. Gen. 3:1401–1403.PubMedCrossRefGoogle Scholar
  10. 10.
    Bruford, E.A., Mansfield, D.C., Teague, P.W., Barber, A., Fossarello, M., and Wright, A.F., 1994, Genetic linkage studies in autosomal recessive retinitis pigmentosa, Am. J. Hum. Genet. 55:(supplement) A181.Google Scholar
  11. 11.
    Rosenfeld, P.J., Cowley, G.S., McGee, T.L., Sandberg, M.A., Berson, E.L., and Dryja, T.P., 1992, A null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa, Nature Genet. 1:209–213.PubMedCrossRefGoogle Scholar
  12. 12.
    Kumaramanickavel, G., Maw, M., Denton, M.J., John, S., Srisailapathy Srikumari, C.R., Orth, U., Oehlmann, R., and Gal, A., 1994, Missense rhodopsin mutation in a family with recessive RP, Nature Genet. 8:10–11.PubMedCrossRefGoogle Scholar
  13. 13.
    McLaughlin, M.E., Sandberg, M.A., Berson, E.L., and Dryja, T.P., 1993, Recessive mutations in the gene encoding the ß-subunit of rod phosphodiesterase in patients with retinitis pigmentosa, Nature Genet. 4:130–134.PubMedCrossRefGoogle Scholar
  14. 14.
    Riess, O., Noerremoelle, A., Weber, B., Musarella, M.A., and Hayden, M.R., 1992, The search for mutations in the gene for the beta subunit of the cGMP phosphodiesterase (PDEB) in patients with autosomal recessive retinitis pigmentosa, Am. J. Hum. Genet. 51:755–762.PubMedCentralPubMedGoogle Scholar
  15. 15.
    Riess, O., Noerremoelle, A., Collins, C., Mah, D., Weber, B., and Hayden, M.R., 1992, Exclusion of DNA Changes in the β-Subunit of the c-GMP phosphodiesterase gene as the cause for Huntington’s disease, Nature Genet. 1:104–108.PubMedCrossRefGoogle Scholar
  16. 16.
    Pittler, S.J., and Baehr W., 1991, Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase β-subunit gene of the rd mouse, Proc. Natl. Acad. Sci. USA 88:8322–8326.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Suber, M.L. Pittler, S.J., Qin, N., Wright, G.C., Holcombe, V, Lee, R.H., Craft, M., Lolley, R.N., Baehr, W., and Hurwitz, R.L., 1993, Irish setter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase β-subunit gene, Proc. Natl. Acad. Sci. USA 90:3968–3972.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Portera-Cailliau, C., Sung, C.-H., Nathans, J., and Adler, R., 1994, Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa, Proc. Natl. Acad. Sci. USA 91:974–978.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Khramtsov, N.V., Feschenko, E.A., Suslova, V.A., Shmukler, B.E., Terpugov, B.E., Rakitina, T.V., Atabekova, N.V., and Lipkin, V.M., 1993, The human rod photoreceptor cGMP phosphodiesterase ß-subunit, FEBS Letters 327:275–278.PubMedCrossRefGoogle Scholar
  20. 20.
    Kajiwara, K., Berson, E.L., and Dryja, T.P., 1994, Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci, Science 264:1604–1608.PubMedCrossRefGoogle Scholar
  21. 21.
    Collins, C., Hutchinson, G., Kowbel, D., Riess, O., Weber, B., and Hayden, M., 1992, The human ß-subunit of rod photoreceptor cGMP phosphodiesterase: complete retinal cDNA sequence and evidence for expression in brain, Genomics 13:698–704.PubMedCrossRefGoogle Scholar
  22. 22.
    Seabra, M.C., Brown, M.S., Slaughter, A., Südhof, T.C., and Goldstein, J.L., 1992, Purification of component A of Rab geranylgeranyl transferase: Possible identity with the choroideremia gene product, Cell 70:1049–1057.PubMedCrossRefGoogle Scholar
  23. 23.
    Dryja, T.P., Berson, E.L., Rao, V.R. and Oprian, D.D., 1993, Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness, Nature Genet. 4:280–283.PubMedCrossRefGoogle Scholar
  24. 24.
    Sieving, P.A., Richards, J.E., Naarendorp, F., Bingham, E., Scott, K. and Alpern, M., 1995, Dark-light: Model for nightblindness from the human rhodopsin Gly-90 → Asp mutation, Proc. Natl. Acad. Sci. USA 92:880–884.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Rao, V.R., Cohen G.B. and Oprian, D.D., 1994, Rhodopsin mutation G90D and a molecular mechanism for congenital night blindness, Nature 367:639–642.PubMedCrossRefGoogle Scholar
  26. 26.
    Rambusch, S.H.A., 1909, Den medfodte Natteblindheds Arvelighedsforhold, Oversigt over det Kgl. Danske Videnskabernes Selskabs Forhandlinger 3:337–347.Google Scholar
  27. 27.
    Gal, A., Xu, S., Piczenik, Y, Eiberg, H., Duvigneau, C., Schwinger, E. and Rosenberg, T., 1994, Gene for autosomal dominant congenital stationary night blindness maps to the same region as the gene for the ß-subunit of the rod photoreceptor cGMP phosphodiesterase (PDEB) in chromosome 4p16.3, Hum. Mol. Genet. 3:323–325.PubMedCrossRefGoogle Scholar
  28. 28.
    Rosenberg, T., Gal, A. and Simonsen, S.E., 1995, ERG findings in two patients with autosomal dominant congenital stationary night blindness and His258Asn mutation of the ß-subunit of rod photoreceptor cGMP-specific phosphodiesterase. This volume.Google Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • A. Veske
    • 1
  • U. Orth
    • 1
  • K. Rüther
    • 2
  • E. Zrenner
    • 2
  • T. Rosenberg
    • 3
  • W. Baehr
    • 4
  • A. Gal
    • 1
  1. 1.Institut für HumangenetikUniversitäts-Krankenhaus EppendorfHamburgGermany
  2. 2.Augenklinik der Universität, Abteilung IITübingenGermany
  3. 3.National Eye Clinic for the Visually ImpairedHellerupDenmark
  4. 4.Department of OphthalmologyCullen Eye Institute, Baylor College of MedicineHoustonUSA

Personalised recommendations