Search tips
Search criteria 


Logo of narLink to Publisher's site
Nucleic Acids Res. 1988 March 25; 16(5 Pt B): 2099–2110.
PMCID: PMC338202

Correction of mouse ornithine transcarbamylase deficiency by gene transfer into the germ line.


The sparse fur with abnormal skin and hair (Spf-ash) mouse is a model for the human X-linked hereditary disorder, ornithine transcarbamylase (OTC) deficiency. In Spf-ash mice, both OTC mRNA and enzyme activity are 5% of control values resulting in hyperammonemia, pronounced orotic aciduria and an abnormal phenotype characterized by growth retardation and sparse fur. Using microinjection, we introduced a construction containing rat OTC cDNA linked to the SV40 early promoter into fertilized eggs of Spf-ash mice. The expression of the transgene resulted in the development of a transgenic mouse whose phenotype and orotic acid excretion are fully normalized. Thus, the possibility of correcting hereditary enzymatic defect by gene transfer of heterologous cDNA coding for the normal enzyme has been demonstrated.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Palmiter RD, Brinster RL. Germ-line transformation of mice. Annu Rev Genet. 1986;20:465–499. [PubMed]
  • Soriano P, Cone RD, Mulligan RC, Jaenisch R. Tissue-specific and ectopic expression of genes introduced into transgenic mice by retroviruses. Science. 1986 Dec 12;234(4782):1409–1413. [PubMed]
  • Palmiter RD, Brinster RL. Transgenic mice. Cell. 1985 Jun;41(2):343–345. [PubMed]
  • Short EM, Conn HO, Snodgrass PJ, Campbell AG, Rosenberg LE. Evidence for x-linked dominant inheritance of ornithine transcarbamylase deficiency. N Engl J Med. 1973 Jan 4;288(1):7–12. [PubMed]
  • Raijman L. Citrulline synthesis in rat tissues and liver content of carbamoyl phosphate and ornithine. Biochem J. 1974 Feb;138(2):225–232. [PubMed]
  • Jackson MJ, Beaudet AL, O'Brien WE. Mammalian urea cycle enzymes. Annu Rev Genet. 1986;20:431–464. [PubMed]
  • DeMars R, LeVan SL, Trend BL, Russell LB. Abnormal ornithine carbamoyltransferase in mice having the sparse-fur mutation. Proc Natl Acad Sci U S A. 1976 May;73(5):1693–1697. [PubMed]
  • Doolittle DP, Hulbert LL, Cordy C. A new allele of the sparse fur gene in the mouse. J Hered. 1974 May-Jun;65(3):194–195. [PubMed]
  • Briand P, Cathelineau L, Kamoun P, Gigot D, Penninckx M. Increase of ornithine transcarbamylase protein in sparse-fur mice with ornithine transcarbamylase deficiency. FEBS Lett. 1981 Jul 20;130(1):65–68. [PubMed]
  • Veres G, Gibbs RA, Scherer SE, Caskey CT. The molecular basis of the sparse fur mouse mutation. Science. 1987 Jul 24;237(4813):415–417. [PubMed]
  • Briand P, Miura S, Mori M, Cathelineau L, Kamoun P, Tatibana M. Cell-free synthesis and transport of precursors of mutant ornithine carbamoyltransferases into mitochondria. Biochim Biophys Acta. 1983 Nov 8;760(3):389–397. [PubMed]
  • Nguyen M, Argan C, Lusty CJ, Shore GC. Import and processing of hybrid proteins by mammalian mitochondria in vitro. J Biol Chem. 1986 Jan 15;261(2):800–805. [PubMed]
  • Bourachot B, Jouanneau J, Giri I, Katinka M, Cereghini S, Yaniv M. Both early and late control sequences of SV40 and polyoma promote transcription of Escherichia coli gpt gene in transfected cells. EMBO J. 1982;1(8):895–900. [PubMed]
  • Gordon JW, Ruddle FH. Gene transfer into mouse embryos: production of transgenic mice by pronuclear injection. Methods Enzymol. 1983;101:411–433. [PubMed]
  • Möröy T, Etiemble J, Trépo C, Tiollais P, Buendia MA. Transcription of woodchuck hepatitis virus in the chronically infected liver. EMBO J. 1985 Jun;4(6):1507–1514. [PubMed]
  • Kamoun P, Coudé M, Deprun C, Rabier D. Source of error in the assay of urinary orotic acid. Clin Chem. 1987 May;33(5):713–713. [PubMed]
  • Snodgrass PJ. The effects of pH on the kinetics of human liver Ornithine--carbamyl phosphate transferase. Biochemistry. 1968 Sep;7(9):3047–3051. [PubMed]
  • Palmiter RD, Wilkie TM, Chen HY, Brinster RL. Transmission distortion and mosaicism in an unusual transgenic mouse pedigree. Cell. 1984 Apr;36(4):869–877. [PubMed]
  • Wagner EF, Covarrubias L, Stewart TA, Mintz B. Prenatal lethalities in mice homozygous for human growth hormone gene sequences integrated in the germ line. Cell. 1983 Dec;35(3 Pt 2):647–655. [PubMed]
  • Wilkie TM, Palmiter RD. Analysis of the integrant in MyK-103 transgenic mice in which males fail to transmit the integrant. Mol Cell Biol. 1987 May;7(5):1646–1655. [PMC free article] [PubMed]
  • Veres G, Craigen WJ, Caskey CT. The 5' flanking region of the ornithine transcarbamylase gene contains DNA sequences regulating tissue-specific expression. J Biol Chem. 1986 Jun 15;261(17):7588–7591. [PubMed]
  • Hata A, Tsuzuki T, Shimada K, Takiguchi M, Mori M, Matsuda I. Isolation and characterization of the human ornithine transcarbamylase gene: structure of the 5'-end region. J Biochem. 1986 Sep;100(3):717–725. [PubMed]
  • Swanson LW, Simmons DM, Arriza J, Hammer R, Brinster R, Rosenfeld MG, Evans RM. Novel developmental specificity in the nervous system of transgenic animals expressing growth hormone fusion genes. Nature. 317(6035):363–366. [PubMed]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press