Abstract
Ornithine transcarbamylase (EC 2.1.3.3.) deficiency (OTCD) is the most common and severe defect of the urea cycle disorders. It is an X-linked disorder with a high new mutation rate and variable phenotypic consequences. The enzyme catalyses the condensation of carbamyl phosphate and ornithine to citrulline in the second step of the urea cycle. It is expressed mainly in the liver and intestine (approximately 30% of liver levels), and is targeted to the mitochondria in which it assumes its homotrimeric active form.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Maestri N., Hauser E., Bartholomew D., Brusilow S.W., 1991, Prospective treatment of urea cycle disorder, J. Pediatr. 119:923–928.
Bmsilow, S. W. and Horwich, A. L. In: The metabolic basis of inherited disease, Vol 6 (Scriver CR, Beaudet AL, Sly WS and Valle D, Eds) New York: McGraw-Hill, pp 629–670. (1989)
Finkelstein J., Hauser E., Leonard C., Brusilow S., 1990, Late-onset ornithine transcarbamylase deficiency in male patients, J. Pediatr. 117(6):(6)897–902.
Batshaw M., Msall M., Beaudate A., Trojak J., 1986, Risk of serious illness in heterozygotes for Ornithin Transcarbamylase deffeciency, J. Pediatr. 108:236–241.
Rowe P., Newman S., Brusilow S.W., 1986, Natural history of symptomatic partial ornithine transcarbamylase deficiency, New Engl Med, 314:541–547.
Arn P.H., Hauser E.R., Thomas G.H., Herman G., Hess D., Brusilow S.W., 1990, Hyperammonemia in women with a mutation in the ornithine transcarbamylase locus: a cause of postpartum coma., New Engl J Med, 322:1652–1655.
Morsy M.A., Mitani K., Clemens P., Caskey C.T., 1993, Progress towards human gene therapy,JAMA, 270:2338–2345.
Ponder K.P., Gupta S., Leland F., Darlington G., Finegold M., DeMayo J., Ledley F.D., Chowdhury J.R., Woo S.L.C., 1991, Mouse hepatocytes migrate to liver parenchyma and function indefinitely after intrasplenic transplantation. Proc. Natl. Acad. Sci. USA, 88:1217–1221.
Chowdhury J.R., Grossman M., Gupta S., Chowdhury N.R., Baker J.R. Jr., Wilson J.M., 1991,Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits, Science, 254:1802–1805.
Ledley F.D., Woo S.L.C., Ferry G.D., Whisennand H.H., Brandt M.L., Darlington G.J., Demmler G.J., Finegold M.J., Pokorny W.J., Rosenblatt H., Schwart P., Anderson W.F., Moen R.C., 1991, Clinical protocol: hepatocellular transplantation in acute hepatic failure and targeting genetic markers to hepatic cells, Hum. Gene. Ther., 2:331–358.
Wilson J., Grossman M., Raper S., Baker J.J., Newton R., Thoene J., 1992, Ex vivo gene therapy of familial hypercholesterolemia, Hum. Gene. Ther., 3:179–222.
Cristiano R., Smith L., Kay M., Brinkley B., Woo S., 1993, Hepatic gene therapy: efficient gene delivery and expression in primary hepatocytes utilizing a conjugated adenovirus-DNA complex, Proc. Natl. Acad. Sci. USA, 90:11548–11552.
Human gene marker/therapy clinical protocols, 1994, Hum. Gene Ther., 5(2):271–280.
Graham, F. L. and Prevec, L. Manipulation of adenovirus vectors. In: Methods in Molecular Biology, edited by E.J.Clifton, NJ: The Humana Press Inc., 1991, p. 109–128.
Horwitz, M. S. Field’s Virology (2nd), edited by B. N. Fields and D. M. Knipe, NY: Raven Press,1990, p. 1679–1721.
Quantin, B., Perricaudet, L.D., Tajbakhsh, S., Mandel. J.L., 1992, Adenovirus as an expression vector in muscle cells in vivo, Proc. Natl. Acad. Sci. USA. 89:2581–2584.
Stratford-Perricaudet, L., Makeh, I., Perricaudet, M., Briand, P., 1992, Widespread long-term gene transfer to mouse skeletal muscles and heart, J. Clin. Invest., 90:626–630.
Ragot, T., Vincent, N., Chafey, P., Vigne, E., Gilgenk-Rantz, H., Couton, D., Cartaud, J., Briand,P., Kaplan, J.-C., Perricaudet, M., Kahn, A., 1993, Efficient adenovirus-mediated transfer of a human minidystrophin gene to skeletal muscle of mdx mice, Nature, 361:647–650.
Bout, A., Perricaudet, M., Baskin, G., Imler, J.-L., Scholte, B.J., Pavirani, A., Valerio, D., 1994,Lung gene therapy: in vivo adenovirus-mediated gene transfer to Rhesus monkey airway epithelium, Hum. Gene Ther., 5(1):3–10.
Rich, D.P., Anderson, M.P., Gregory, S.H., Cheng, S.H., Paul, S., Jefferson, D.M., McCann, J.D., Klinger, K.W., Smith, A.E., Welsh, M.J., 1990, Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulator in cystic fibrosis airway epithelial cells. Nature, 347:358–363.
Rosenfeld, M.A., Yoshimura, K., Trapnell, B.C., Yoneyama, K., Rosenthal, W., Dalemans, W.,Fukayama, M., Bargon, J., Stier, L.E., Stratford-Perricaudet, L., et al. ., 1992, In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epitheluim. Cell, 68:143–155.
Stratford-Perricaudet, L.D., Levrero, M., Chasse, J.-F., Perricaudet, M., Briand, P., 1990,Evaluation of the Transfer and Expression in Mice of an Enzyme-Encoding Gene Using a Human Adenovirus Vector. Hum. Gene Ther., 1:241–256.
Kozarsky K., Grossman M., Wilson J.M., 1993, Adenovirus-mediated correction of the genetic defect in hepatocytes from pateints with familial hypercholesterolemia, Somat. Cell Mol. Genet, 19:449–458.
Ishibashi S., Brown M.S., Goldstein J.L., Gerard R.D., Hammer R.E., Herz J., 1993,Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery, J. Clin. Invest., 92:883–893.
Kay M.A., Landen C.N., Rothenberg S.R., Taylor LA., Leland F., Wiehle S., Fang B., Bellinger D., Finegold M., Thompson A.R., Read M., Brinkhous K.M., Woo S.L., 1994, In vivo hepetic gene therapy: complete albeit transeint correction of factor IX deficiency in hemophilia B dogs, Proc. Natl. Acad. Sci. USA, 91:2353–2357.
Gushiken T., Yoshimura N., Saheki T., 1985, Transient hyperammonemia during ageing in ornithine transcarbamylase-deficient, sparse-fur mice, Biochem. Int., 11:637–643.
DeMars R., LeVan S.L., Trend B.L., Russell L.B., 1976, Abnormal ornithine carbamoyltransferase in mice having the sparse-fur mutation, Proc. Natl. Acad. Sci. USA, 73:1693–1697.
Briand P., Cathelineau L., Kamoun P., Gigot D., Penninckx M., 1981, Increase in ornithine transcarbamylase protein in sparse-fur mice with ornithine transcarbamylase deficiency, FEBS lett., 130:65–68.
Hulbert, L., Cordy, C. & Doolittle, D., 1974, A new allele of the sparse fur gene in the mouse,J. Hered., 65:194–195.
Hodges, P. E. & Rosenberg, L. E., 1989, The spfash mouse: A missence mutation in the ornithine transcarbamylase gene also causes aberrant mRNA splicing, Proc. Natl. Acad. Sci. USA, 86:4142–4146.
Jones S.N., Grompe M., Munir M.I., Veres G., Craigen W.J., Caskey C.T., 1990, Ectopic correction of ornithine transcarbamylase deficiency in sparse fur mice, J. Biol. Chem., 265:14684–14690.
Carvard C., Grimber G., Dubois N., Chasse J.F., Bennoun M., Minet T.M., Kamoun P., Briand P., 1988, Correction of mouse ornithine transcarbamylase deficiency by gene transfer into the germ line, Nucl. Acids. Res., 16:2099–2110.
Grompe M., Jones S.N., Loulseged H., Caskey C.T., 1992, Retroviral-mediated gene transfer of human ornithine transcarbamylase into primary hepatocytes of spf and spf-ash mice, Hum. Gene Ther., 3:35–44.
Takebe Y., Seiki M., J.-I. F., P. H., Yokota K., Arai K.-I., Yoshida M., Arai M., SRa promoter:an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-US segment of human T-cell leukemia virus type-1 long terminal repeat, Mol. Cell. Biol., 8:466–472.
Morsy M.A., Alford E.L., Bett A., Graham F.L., Caskey C.T., 1993, Efficient adenoviral-mediated OTC expression in deficient mouse and human hepatocytes, J. Clin. Invest., 92:1580–1586.
MacGregor, G. R. and Caskey, C. T., 1989, Construction of plasmids that express E. coli ß-galactosidase in mammalian cells, Nucl. Acids. Res., 17:2365.
Quershi, I. A., Letarte, J., Ouellet, R., 1979, Ornithine transcarbamylase deficiency in mutant mice:Studies on the charecterization of enzyme defect and suitability as animal models of human disease, Pediatr. Res., 13:807–811.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1994 Springer Science+Business Media New York
About this chapter
Cite this chapter
Morsy, M.A., Caskey, C.T. (1994). Ornithine Transcarbamylase Deficiency: A Model for Gene Therapy. In: Felipo, V., Grisolia, S. (eds) Hepatic Encephalopathy, Hyperammonemia, and Ammonia Toxicity. Advances in Experimental Medicine and Biology, vol 368. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1989-8_15
Download citation
DOI: https://doi.org/10.1007/978-1-4615-1989-8_15
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-5820-6
Online ISBN: 978-1-4615-1989-8
eBook Packages: Springer Book Archive