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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1990 Nov;47(5):790–794.

Splicing defect at the ornithine aminotransferase (OAT) locus in gyrate atrophy.

A I McClatchey 1, D L Kaufman 1, E L Berson 1, A J Tobin 1, V E Shih 1, J F Gusella 1, V Ramesh 1
PMCID: PMC1683684  PMID: 2220818

Abstract

Gyrate atrophy (GA), a recessive eye disease involving progressive vision loss due to chorioretinal degeneration, is associated with the deficiency of the mitochondrial enzyme ornithine aminotransferase (OAT), with consequent hyperornithinemia. We and others have reported a number of missense mutations at the OAT locus which result in GA. Here we report a GA patient of Danish/Swedish ancestry in whom one OAT allele produces an mRNA that is missing a single 96-bp exon relative to the normal mRNA. Polymerase-chain-reaction amplification and sequencing revealed a 9-bp deletion covering the splice acceptor region of exon 5, resulting in the absence of exon 5 sequences from the mRNA with no disruption to the reading frame. This mutation, which was not present in 15 other independent GA patients, adds to the array of allelic heterogeneity observed in GA and represents the first example of a splicing mutation associated with this disorder.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barrett D. J., Bateman J. B., Sparkes R. S., Mohandas T., Klisak I., Inana G. Chromosomal localization of human ornithine aminotransferase gene sequences to 10q26 and Xp11.2. Invest Ophthalmol Vis Sci. 1987 Jul;28(7):1037–1042. [PubMed] [Google Scholar]
  2. Berson E. L., Schmidt S. Y., Shih V. E. Ocular and biochemical abnormalities in gyrate atrophy of the choroid and retina. Ophthalmology. 1978 Oct;85(10):1018–1027. doi: 10.1016/s0161-6420(78)35588-3. [DOI] [PubMed] [Google Scholar]
  3. Chen E. Y., Seeburg P. H. Supercoil sequencing: a fast and simple method for sequencing plasmid DNA. DNA. 1985 Apr;4(2):165–170. doi: 10.1089/dna.1985.4.165. [DOI] [PubMed] [Google Scholar]
  4. Fagan R. J., Sheffield W. P., Rozen R. Regulation of ornithine aminotransferase in retinoblastomas. J Biol Chem. 1989 Dec 5;264(34):20513–20517. [PubMed] [Google Scholar]
  5. Gusella J., Varsanyi-Breiner A., Kao F. T., Jones C., Puck T. T., Keys C., Orkin S., Housman D. Precise localization of human beta-globin gene complex on chromosome 11. Proc Natl Acad Sci U S A. 1979 Oct;76(10):5239–5242. doi: 10.1073/pnas.76.10.5239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Inana G., Chambers C., Hotta Y., Inouye L., Filpula D., Pulford S., Shiono T. Point mutation affecting processing of the ornithine aminotransferase precursor protein in gyrate atrophy. J Biol Chem. 1989 Oct 15;264(29):17432–17436. [PubMed] [Google Scholar]
  7. Inana G., Totsuka S., Redmond M., Dougherty T., Nagle J., Shiono T., Ohura T., Kominami E., Katunuma N. Molecular cloning of human ornithine aminotransferase mRNA. Proc Natl Acad Sci U S A. 1986 Mar;83(5):1203–1207. doi: 10.1073/pnas.83.5.1203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kennaway N. G., Weleber R. G., Buist N. R. Gyrate atrophy of the choroid and retina with hyperornithinemia: biochemical and histologic studies and response to vitamin B6. Am J Hum Genet. 1980 Jul;32(4):529–541. [PMC free article] [PubMed] [Google Scholar]
  9. Marvit J., DiLella A. G., Brayton K., Ledley F. D., Robson K. J., Woo S. L. GT to AT transition at a splice donor site causes skipping of the preceding exon in phenylketonuria. Nucleic Acids Res. 1987 Jul 24;15(14):5613–5628. doi: 10.1093/nar/15.14.5613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Mitchell G. A., Brody L. C., Looney J., Steel G., Suchanek M., Dowling C., Der Kaloustian V., Kaiser-Kupfer M., Valle D. An initiator codon mutation in ornithine-delta-aminotransferase causing gyrate atrophy of the choroid and retina. J Clin Invest. 1988 Feb;81(2):630–633. doi: 10.1172/JCI113365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Mitchell G. A., Brody L. C., Sipila I., Looney J. E., Wong C., Engelhardt J. F., Patel A. S., Steel G., Obie C., Kaiser-Kupfer M. At least two mutant alleles of ornithine delta-aminotransferase cause gyrate atrophy of the choroid and retina in Finns. Proc Natl Acad Sci U S A. 1989 Jan;86(1):197–201. doi: 10.1073/pnas.86.1.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Mitchell G. A., Looney J. E., Brody L. C., Steel G., Suchanek M., Engelhardt J. F., Willard H. F., Valle D. Human ornithine-delta-aminotransferase. cDNA cloning and analysis of the structural gene. J Biol Chem. 1988 Oct 5;263(28):14288–14295. [PubMed] [Google Scholar]
  13. Mitchell P. J., Urlaub G., Chasin L. Spontaneous splicing mutations at the dihydrofolate reductase locus in Chinese hamster ovary cells. Mol Cell Biol. 1986 Jun;6(6):1926–1935. doi: 10.1128/mcb.6.6.1926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mullis K. B., Faloona F. A. Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Methods Enzymol. 1987;155:335–350. doi: 10.1016/0076-6879(87)55023-6. [DOI] [PubMed] [Google Scholar]
  15. O'Donnell J. J., Sandman R. P., Martin S. R. Gyrate atrophy of the retina: inborn error of L-ornithin:2-oxoacid aminotransferase. Science. 1978 Apr 14;200(4338):200–201. doi: 10.1126/science.635581. [DOI] [PubMed] [Google Scholar]
  16. O'Donnell J. J., Vannas-Sulonen K., Shows T. B., Cox D. R. Gyrate atrophy of the choroid and retina: assignment of the ornithine aminotransferase structural gene to human chromosome 10 and mouse chromosome 7. Am J Hum Genet. 1988 Dec;43(6):922–928. [PMC free article] [PubMed] [Google Scholar]
  17. Ramesh V., Benoit L. A., Crawford P., Harvey P. T., Shows T. B., Shih V. E., Gusella J. F. The ornithine aminotransferase (OAT) locus: analysis of RFLPs in gyrate atrophy. Am J Hum Genet. 1988 Feb;42(2):365–372. [PMC free article] [PubMed] [Google Scholar]
  18. Ramesh V., Eddy R., Bruns G. A., Shih V. E., Shows T. B., Gusella J. F. Localization of the ornithine aminotransferase gene and related sequences on two human chromosomes. Hum Genet. 1987 Jun;76(2):121–126. doi: 10.1007/BF00284906. [DOI] [PubMed] [Google Scholar]
  19. Ramesh V., McClatchey A. I., Ramesh N., Benoit L. A., Berson E. L., Shih V. E., Gusella J. F. Molecular basis of ornithine aminotransferase deficiency in B-6-responsive and -nonresponsive forms of gyrate atrophy. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3777–3780. doi: 10.1073/pnas.85.11.3777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ramesh V., Shaffer M. M., Allaire J. M., Shih V. E., Gusella J. F. Investigation of gyrate atrophy using a cDNA clone for human ornithine aminotransferase. DNA. 1986 Dec;5(6):493–501. doi: 10.1089/dna.1.1986.5.493. [DOI] [PubMed] [Google Scholar]
  21. Shih V. E., Berson E. L., Mandell R., Schmidt S. Y. Ornithine ketoacid transaminase deficiency in gyrate atrophy of the choroid and retina. Am J Hum Genet. 1978 Mar;30(2):174–179. [PMC free article] [PubMed] [Google Scholar]
  22. Treisman R., Proudfoot N. J., Shander M., Maniatis T. A single-base change at a splice site in a beta 0-thalassemic gene causes abnormal RNA splicing. Cell. 1982 Jul;29(3):903–911. doi: 10.1016/0092-8674(82)90452-4. [DOI] [PubMed] [Google Scholar]
  23. Tromp G., Prockop D. J. Single base mutation in the pro alpha 2(I) collagen gene that causes efficient splicing of RNA from exon 27 to exon 29 and synthesis of a shortened but in-frame pro alpha 2(I) chain. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5254–5258. doi: 10.1073/pnas.85.14.5254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Yandell D. W., Campbell T. A., Dayton S. H., Petersen R., Walton D., Little J. B., McConkie-Rosell A., Buckley E. G., Dryja T. P. Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling. N Engl J Med. 1989 Dec 21;321(25):1689–1695. doi: 10.1056/NEJM198912213212501. [DOI] [PubMed] [Google Scholar]

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