Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1989 Jan;86(1):197–201. doi: 10.1073/pnas.86.1.197

At least two mutant alleles of ornithine delta-aminotransferase cause gyrate atrophy of the choroid and retina in Finns.

G A Mitchell 1, L C Brody 1, I Sipila 1, J E Looney 1, C Wong 1, J F Engelhardt 1, A S Patel 1, G Steel 1, C Obie 1, M Kaiser-Kupfer 1, et al.
PMCID: PMC286431  PMID: 2492100

Abstract

Gyrate atrophy of the choroid and retina (GA) is an inherited chorioretinal degeneration caused by deficiency of ornithine delta-aminotransferase (OAT; L-ornithine: 2-oxo-acid aminotransferase; EC 2.6.1.13). GA is one of the "Finnish genetic diseases," a group of several rare monogenic disorders that occur with increased frequency in the Finnish population. Using a combination of RNase A protection, genomic cloning, and polymerase chain reaction amplification of genomic DNA, we found one of two missense mutant OAT alleles to be present in each of 16 Finnish GA pedigrees. The first mutation R180T, in which arginine-180 is replaced by threonine, was present in homozygous form in patients from two pedigrees. The second mutation L402P, in which leucine-402 is replaced by proline, was present in homozygous form in patients from 14 pedigrees. Neither mutation was present in 19 Finnish controls. L402P was not present in 18 non-Finnish GA patients but R180T was found in an American GA patient. We constructed full-length mutant cDNAs by amplifying patient cDNA with the polymerase chain reaction and cloning a restriction fragment containing the mutation into an otherwise normal human OAT cDNA. These mutant cDNAs were then expressed in CHO-K1 cells, which lack endogenous OAT. Both R180T and L402P inactivate OAT. These results show molecular heterogeneity in GA alleles even in the Finnish population.

Full text

PDF
197

Images in this article

198Image
on p.198
198Image
on p.198
199Image
on p.199
199Image
on p.199
199Image
on p.199
199Image
on p.199
199Image
on p.199
199Image
on p.199
200Image
on p.200
200Image
on p.200
200Image
on p.200
200Image
on p.200
200Image
on p.200
200Image
on p.200
200Image
on p.200

Selected References

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

  1. Arpaia E., Dumbrille-Ross A., Maler T., Neote K., Tropak M., Troxel C., Stirling J. L., Pitts J. S., Bapat B., Lamhonwah A. M. Identification of an altered splice site in Ashkenazi Tay-Sachs disease. Nature. 1988 May 5;333(6168):85–86. doi: 10.1038/333085a0. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Chen C., Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. doi: 10.1128/mcb.7.8.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Degols G. Functional analysis of the regulatory region adjacent to the cargB gene of Saccharomyces cerevisiae. Nucleotide sequence, gene fusion experiments and cis-dominant regulatory mutation analysis. Eur J Biochem. 1987 Nov 16;169(1):193–200. doi: 10.1111/j.1432-1033.1987.tb13597.x. [DOI] [PubMed] [Google Scholar]
  5. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  6. Hall C. V., Jacob P. E., Ringold G. M., Lee F. Expression and regulation of Escherichia coli lacZ gene fusions in mammalian cells. J Mol Appl Genet. 1983;2(1):101–109. [PubMed] [Google Scholar]
  7. 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]
  8. 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]
  9. Myerowitz R. Splice junction mutation in some Ashkenazi Jews with Tay-Sachs disease: evidence against a single defect within this ethnic group. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3955–3959. doi: 10.1073/pnas.85.11.3955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ohno K., Suzuki K. A splicing defect due to an exon-intron junctional mutation results in abnormal beta-hexosaminidase alpha chain mRNAs in Ashkenazi Jewish patients with Tay-Sachs disease. Biochem Biophys Res Commun. 1988 May 31;153(1):463–469. doi: 10.1016/s0006-291x(88)81247-6. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. 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]
  13. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Simell O., Takki K. Raised plasma-ornithine and gyrate atrophy of the choroid and retina. Lancet. 1973 May 12;1(7811):1031–1033. doi: 10.1016/s0140-6736(73)90667-3. [DOI] [PubMed] [Google Scholar]
  15. Smith P. K., Krohn R. I., Hermanson G. T., Mallia A. K., Gartner F. H., Provenzano M. D., Fujimoto E. K., Goeke N. M., Olson B. J., Klenk D. C. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985 Oct;150(1):76–85. doi: 10.1016/0003-2697(85)90442-7. [DOI] [PubMed] [Google Scholar]
  16. Sullivan K. F., Cleveland D. W. Identification of conserved isotype-defining variable region sequences for four vertebrate beta tubulin polypeptide classes. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4327–4331. doi: 10.1073/pnas.83.12.4327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Valle D., Downing S. J., Harris S. C., Phang J. M. Proline biosynthesis: multiple defects in Chinese hamster ovary cells. Biochem Biophys Res Commun. 1973 Aug 21;53(4):1130–1136. doi: 10.1016/0006-291x(73)90582-2. [DOI] [PubMed] [Google Scholar]
  18. Valle D., Kaiser-Kupfer M. I., Del Valle L. A. Gyrate atrophy of the choroid and retina: deficiency of ornithine aminotransferase in transformed lymphocytes. Proc Natl Acad Sci U S A. 1977 Nov;74(11):5159–5161. doi: 10.1073/pnas.74.11.5159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Wong G. G., Witek J. S., Temple P. A., Wilkens K. M., Leary A. C., Luxenberg D. P., Jones S. S., Brown E. L., Kay R. M., Orr E. C. Human GM-CSF: molecular cloning of the complementary DNA and purification of the natural and recombinant proteins. Science. 1985 May 17;228(4701):810–815. doi: 10.1126/science.3923623. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES