Abstract
Literature on sparse-fur (spf) mutant mouse, as an animal model of congenital hyperammonemia has been reviewed earlierl,4. Our current estimates indicate that over one hundred full-fledged articles have been published on spf mice since 1976, when the X-linked hepatic ornithine transcarbamylase (OTC; E.C. 2.1.3.3.) deficiency associated with the sparse-fur mutation was described for the first time5. An allelic form, the spfash (abnormal skin and hair) mutation, having a somewhat different phenotype to spf mouse, was also shown to have a quantitative deficiency of the hepatic OTC6. These publications have covered various aspects of the expression of the spf gene, including the clinical pathology, neurochemical pathology, behavior, experimental carcinogenesis and pharmacogenetics. Moreover, the spf mouse is now established as an animal model to study the effects of transgenic and viral-mediated gene therapy7,12. As indicated in Figure. 1, this has brought in a dramatic increase in new research studies on the spf and spfash mice, a big majority of which were initiated from our laboratory. It can be said that the spf mouse is now established as the most appropriate model to study the pathology and therapy of chronic hyperammonemic encephalopathy, particularly of hereditary origin. In the following text, we shall briefly review the nature and expression of the spf mutation, at the hepatic and intestinal levels, and its similarity to the human OTC deficiency. Particular emphasis shall be given to the neurochemical pathology in the spf mouse, from the point of view of metabolic and neurotransmitter abnormalities.
Keywords
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.
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
I.A. Qureshi, J. Letarte, and S.R. Qureshi, Congenital hyperammonemia (Model No. 235), in: Handbook of Animal Models of Human Disease, C. C. Capen, D. B Hackle, T. C Jones, G. Migaki ed., Fase 11. Washington, D.C: Registry of Comparative Pathology, pp 2–4 (1981).
M.L. Batshaw, S.L. Hyman, C. Bachmann, I.A. Qureshi and J.T. Coyle, Animal Models of congenital hyperammonemia, in: Animal Models of Dementia, J.T.Coyle, ed., Alan. R. Liss, Inc, New York, pp 163–198 (1987).
I.A. Qureshi, Congenital hyperammonemia (Model No. 235) Supplemetal Update, in: Handbook of Animal Models of Human Disease, C. C. Capen, D. B Hackle, T. C Jones, G. Migaki, ed., Fase 11. Washington, D.C: Registry of Comparative Pathology, pp 1–2 (1989).
I.A. Qureshi, Animal models of hereditary hyperammonemias, in: Neuromethods, Animal Models of Neurological Disease, II, A. Boulton., G. Baker and R. Butterworth, ed., The Humana Press Inc, New York pp 329–356 (1992).
R. Demars, S.L. LeVan, B.L. Trend and L.B. Russel, Abnormal ornithine carbamoyl-transferase in mice having the sparse-fur mutation. Proc. Natl. Acad. Sci, U.S.A. 73:1693–1698 (1976).
I.A. Qureshi, J. Letarte and R. Ouellet, Spontaneous animal models of ornithine transcarbamylase deficiency: Studies on serum and urinary nitrogen metabolites, in: Urea Cycle Diseases, A. Lowenthal, A. Mori and B. Marecau, ed., Plenum Press, New York, pp 173–183 (1983).
M.L. Batshaw, M. Yudkoff, B.A. McLaughlin, E. Gorry, N.J. Anegawa, I.A.S. Smith and M.B. Robinson, The sparse-fur mouse as a model of gene therapy in ornithine carbamoyltransferase deficiency, Gene Therapy. 2:743–749 (1995).
J.C. Pages, M. Andreoletti, M. Bennoun, C. Vons, J. Elcheroth, P. Lehn, D. Houssin, J. Chapman, P. Briand, R. Benarous, D. Franco and A. Weber, Efficient retroviral-mediated gene transfer into primary cultures of murine and human hepatocytes: Expression of LDL receptor, Human Gene Therapy 6:21–30 (1995).
S.E. Raper, Hepatocyte transplantation and gene therapy, Clin Transplantation. 9:249–254 (1995).
M.A. Morsy and C.T. Caskey, Ornithine transcarbamylase deficiency: A model for gene therapy, in: Hepatic Encephalopathy, Hyperammonemia, and Ammonia Toxicity, V. Felipo and S. Grisolia, ed., Plenum Press, New York, pp 145–154 (1994).
M.A. Morsy, J.Z. Zhao, T.T. Ngo, A.W. Warman, W.E. O’Brien and F.L. Graham, Patient selection may affect gene therapy success, J. Clin. Invest. 97:826–831 (1996).
X. Ye, M.B. Robinson, M.L. Batshaw, E.E. Furth, I. Smith and J.M. Wilson, Prolonged metabolic correction in adult ornithine transcarbamylase-deficient mice with adenoviral vectors, J. Biol. Chem. 271:3639–3646 (1996).
I.A. Qureshi, J. Letarte and R. Ouellet, Ornithine transcarbamylase deficiency in mutant mice I. Studies on the characterization of enzyme defect and suitability as animal model of human disease, Pediat. Res. 13:807–811 (1979).
G. Veres, R.A. Gibbs, S.E. Scherer and C.T. Caskey, The molecular basis of sparse-fur mouse mutation, Science. 237:415–417 (1987).
N.S. Cohen, C.W. Cheung and L. Raijman, Altered enzyme activities and citrulline synthesis in liver mitochondria from ornithine carbamoyltransferase-deficient sparse-furash mice, Biochem. J. 257:251–257 (1989).
P. Briand, S. Mirira, M. Mori, L. Cathelineau, P. Kamoun and M. Talibana, Cell-free synthesis and transport of precursors of mutant ornithine carbamoyltransferases into mitochondria, Biochem. Biophys. Acta, 760:389–397 (1983).
A. Ohtake, M. Takayanagi, S. Yamamoto, H. Nakajima and M. Mori, Ornithine transcarbamylase deficiency in spf and spf-ash mice: Genes, mRNA and mRNA precursors, Biochem. Biophys. Res. Commun. 146:1064–1070 (1987).
N. Dubois, C. Cavard, J.F. Chasse, P. Kamoun and P. Briand, Compared expression of ornithine transcarbamylase and carbamyl phosphate synthetase in liver and small intestine of normal and mutant mice, Biochim. Biophys. Acta. 950:321–328 (1988).
Y.R. Mawal, K.V. RamaRao and I.A. Qureshi, Enhanced expression of hepatic mitochondrial urea cycle enzymes and cytochrome C oxidase with chronic acetyl-L-carnitine treatment in spf mice with ornithine transcarbamylase deficiency, J. Biol. Chem. (submitted) (1996).
A. Russel, B. Levin, V.G. Oberholzer and L. Sinclair, Hyperammonemia. A new instance of an inborn enzymatic defect of the biosynthesis of urea, Lancet. 2:699–700 (1962).
E.M. Short, HO. Conn, P.I. Snodgrass, A.G.M. Campbell and L.E. Rosenberg, Evidence for X-linked dominant inheritance of ornithine transcarbamylase deficiency, N. Engl. J. Med. 288:7–12 (1973).
P. Briand, B. Francois, D. Rabier and L. Cathelineau, Omithine transcarbamylase deficiencies in human males: Kinetic and immunochemical classification, Biochem. Biophys. Acta. 704:100–106 (1982).
I.A. Qureshi, J. Letarte and R. Ouellet, Expression of ornithine transcarbamylase deficiency in the small intestine and colon of sparse-fur mutant mice, J. Pediatr. Gastroenterol. Nutr. 4:118–124 (1985).
E.S. Spector and R.A. Mazzochi, The sparse-fur mouse: An animal model for a human inborn error of metabolism of the urea cycle, in: Orphan Drugs and Orphan Diseases: Clinical Realities and Public Policy, Alan R. Liss, Inc, New York, pp 86–96 (1983).
I.A. Qureshi, J. Letarte and R. Ouellet, Activity of orotate metabolizing enzyme complex and various urea cycle enzymes in mutant mice with ornithine trans-carbamylase deficiency, Experientia. 38:308–309 (1982).
S. Vasudevan, I.A. Qureshi, L. Mores, P.M. Rao, S. Rajalakshmi and D.S.R. Sarma, Abnormal hepatic nucleotide pools in sparse-fur (spf) mutant mice deficient in ornithine transcarbamylase, Biochem Med. Metabol. Biol. 47:274–278 (1992).
L. Vasudevan, I.A. Qureshi, M. Lambert, P. Rao, S. Rajalakshmi and D.S.R. Sarma, Nucleotide pool imbalances in the livers of patients with urea cycle disorders associated with increased levels of orotic acid, Biochem. Mol. Biol. Int. 35:685–690 (1995).
I.A. Qureshi, J. Letarte, S. Lebel and R. Ouellet, Variablite de l’active enzymatique et de l’acidurie orotique chez les souris spf/+ heterozygotes deficientes en ornithine transcarbamylase, Diabete. Metabolisme. 12:250–255 (1986).
J.C. Feoli-Fonseca, M. Lambert, G. Mitchell, S.B. Melançon, L. Dallaire, D.S. Millington and I.A. Qureshi, Chronic sodium benzoate therapy in children with inborn errors of urea synthesis: Effect on carnitine metabolism and ammonia nitrogen removal, Biochem. Mol. Med. 57:31–36 (1996).
A. Michalak and I.A. Qureshi, Carnitine musculaire chez les souris hyperammoniémiques: effect du traitement au benzoate de sodium, Can. J. Physiol. Pharmacol. 71:439–446 (1990).
A. Michalak and I.A. Qureshi, Profil des acylcarnitines hepatiques et musculares chez les souris chroniquement hyperammonemiques apres un traitment aigu avec le benzoate de sodium: etudes dose-response, Ann Biol Clin. 50:879–885 (1993).
I. Inoue, T. Gushiken, K. Kobayashi and T. Saheki, Accumulation of large neutral amino acids in the brains of sparse-fur mice at hyperammonemic state, Biochem Med. Metabol. Biol. 38:378–386 (1987).
L. Ratnakumari, I.A. Qureshi and R.F. Butterworth, Effects of congenital hyperammonemia on the cerebral and hepatic levels of the intermediates of energy metabolism in spf mice, Biochem. Biophys. Res. Commn. 184:746–751 (1992).
L. Ratnakumari, I.A. Qureshi and R.F. Butterworth, Effect of sodium benzoate on cerebral and hepatic energy metabolites in spf mice with congenital hyperammonemia, Biochem. Pharmacol. 45:137–146 (1993).
L. Ratnakumari, I.A. Qureshi and R.F. Butterworth, Regional amino acid neuro-transmitter changes in brains of spf/Y mice with congenital omithine transcarbamylase deficiency, Metabol Brain Dis. 9:43–51 (1994).
L. Ratnakumari, I.A. Qureshi, R.F. Butterworth, B. Marescau and P.P. De Deyn, Arginine-related guanidino compounds and nitric oxide synthase in brain of ornithine transcarbamylase deficient spf mutant mouse: Effect of metabolic arginine deficiency, Neurosci. Lett. 215:153–156 (1996).
M.L. Batshaw, S.L. Human, J.T. Coyle, M.B. Robinson, I.A. Qureshi, E.D. Mellits and S. Quaskey, Effect of sodium benzoate and sodium phenylacetate on brain serotonin turnover in the omithine transcarbamylasedeficient sparse-fur mouse, Pediatr. Res. 23:368–374 (1988).
A. Conelly, J.H. Cross, D.G. Gadien, J.V Hunter, F.J. Kirkham and J.V. Leonard, Magnetic resonance spectrocopy shows increased brain glutamine in ornithine trans-carbamylase deficiency, Pediatr. Res. 33:77–81 (1993).
S.W. Brusilow and A.L. Horwich, Urea cycle enzymes, in: Metabolic and Molecular Bases of Inherited Disease, C.R. Scriver, A.L. Beaudet, W.S. Sly and D. Valle ed., McGraw Hill, New York, pp 1187–1232, (1995).
J.F. Giguere and R.F. Butterworth, Amino acid changes in regions of CNS in relation to function in experimental portal-systemic encephalopathy, Neurochem. Res. 9:1309–1321 (1984).
I.A. Qureshi, B. Marescau, M. Levy, P.P. DeDeyn, J. Letarte and A. Lowenthal, Serum and urinary guanidino compounds in sparse-fur mutant mice with ornithine transcarbamylase deficiency, in: Guanidines 2, A. Mori, B.D. Cohen and H. Koide, ed., Plenum Press, New York, pp 45–51 (1989).
V.L.R. Rao, I.A. Qureshi and R.F. Butterworth, Increased densities of binding sites for peripheral-type benzodiazepine receptor ligand [3H]PK 11195 in congenital ornithine transcarbamylase-deficient sparse-fur mouse, Pediatr. Res. 6:777–780 (1993).
R.R.H. Anholt, Mitochondrial benzodiazepine receptors as potential modulators of intermediary metabolism, Trend. Pharmacol Sci. 7:506–511 (1986).
A.J.L. Cooper and F. Plum, Biochemistry and physiology of brain ammonia, Physiol Rev. 67:440–519 (1987).
K.V. Rama Rao, Y.R. Mawal and I.A. Qureshi, Progressive decrease of cerebral cytochrome C oxidase activity in spf mice: Effect of acetyl-L-carnitine in restoring the ammonia-induced cerebral energy depletion, Neurosci. Lett (accepted with revision) 1996.
L. Ratnakumari, G.Y.C.V. Subbalaxmi and Ch.R.K. Murthy, Acute effects of ammonia on the enzymes of citric acid cycle in rat brain, Neurochem. Int. 8:115–120 (1986).
L. Ratnakumari and Ch.R.K. Murthy, Activities of pyruvate dehydrogenase, enzymes of citric acid cycle and aminotransferases in the subcellular fractions of cerebral cortex in normal and hyperammonemic rats, Neurochem. Res. 14:221–228 (1989).
B. Hindfelt, F. Plum and T.E. Duffy, Effect of acute ammonia intoxication on cerebral energy metabolism in rats with porta-caval shunts, J. Clin. Invest. 59:386–396 (1977).
C. Bachmann and J.P. Colombo, Increased tryptophan and 5-hydroxyindoleacetic acid in the brain of ornithine carbamoyltransferase deficient sparse-fur mice, Pediatr. Res. 18:372–375 (1984).
F. Chaouloff, D. Laude, E. Mignot, P. Kamoun and J.L. Elghozi, Tryptophan and serotonin turnover rate in the brain of genetically hyperammonemic mice, Neurochem. Int. 7:143–153 (1985).
I. Inoue, T. Shimizu, T. Saheki, T. Noda and T. Fukuda, Serotonin-and catecholamine-related substances in the brain of ornithine transcarbamylase-deficient sparse-fur mice in the hyperammonemic state: Comparision of two procedures for obtaining brain extract, decapitation and microwave irradiation, Biochem Med. Metabol Biol, 42:232–239 (1989).
V.L.R. Rao, I.A. Qureshi and R.F. Butterworth, Activities of monoamine oxidase-A and-B are altered in the brains of congenitally hyperammonemic sparse-fur (spf) mice, Neurosci. Lett. 170:27–30 (1994).
M.B. Robinson, N.J. Anegawa, E. Gorry, I.A. Qureshi, J.T. Coyle, I. Lucki and M.L. Batshaw, Brain serotonin2 and serotonin1A receptors are altered in the congenitally hyperammonemic sparse fur mouse, J. Neurochem. 58:1016–1022 (1992).
S.L. Hyman, J.C. Parke and C. Porter, Anorexia and altered serotonin metabolism in a patient with argininosuccinic aciduria, J. Pediatr. 108:705–709 (1986).
M.B. Robinson, K. Hopkins, M.L. Batshaw, B.A. McLaughlin, M.P. Heyes and M.L. Oster-granite, Evidence of excitotoxicity in the brain of the ornithine carbamoyltransferase deficient sparse fur mouse, Dev. Brain. Res. 90:35–44 (1995).
M.L. Batshaw, M.B. Robinson, K. Heyland, S. Djali and M.P. Heyes, Quinolinic acid in children with congenital hyperammonemia, Ann Neurol. 34:676–681 (1993).
M.L. Btashaw, Inborn errors of urea synthesis, Ann Neurol. 35:133–141 (1994).
S.W. Brusilow and A.L. Horwich, Urea cycle enzymes, in: Metabolic and Molecular Bases of Inherited Disease, C.R. Scriver, A. L. Beaudet, W.S. Sly and D. Valle, ed., McGraw Hill, New York, pp 1187–1232 (1995).
D.S. Olton, Dementia: Animal models of the cognitive impairments following damage to the basal forebrain cholinergic system, Brain Res. Bull. 25:499–502 (1990).
L. Ratnakumari, I.A. Qureshi, D. Maysinger and R.F. Butterworth, Developmental deficiency of the cholinergie system in congenitally hyperammonemic spf mice: Effect of acetyl-L-carnitine, J. Pharmacol. Exp. Ther. 274:437–443 (1995).
H.J. Martinez., C.F. Dreyfus., G.M. Jonakait and I.B. Black, Nerve growth factor promotes cholinergic development in brain striatal cultures, Proc. Natl. Acad. Sci. U.S.A. 82: 7777–7781 (1985).
L. Ratnakumari., I.A. Qureshi and R.F. Butterworth, Central muscarinic cholinergic M1 and M2 receptor changes in congenital ornithine transcarbamylase deficiency, Pediatr Res, 40: 25–28 (1996).
L. Ratnakumari., I.A. Qureshi and R.F. Butterworth, Evidence of cholinergic neuronal loss in brain in congenital ornithine transcarbamylase deficiency, Neurosci. Lett, 178: 63–65 (1994).
C.L. Dolman., R.A. Clasen and K. Dorovini-Zis, Severe cerebral damage in ornithine transcarbamylase deficiency, Clin. Neuropathol. 7: 10–15 (1988).
B.N. Harding., J.V. Leonard and M. Erdohazi, Ornithine transcarbamylase deficiency. A neuropathological study, Pediatrics. 141: 215–220 (1984).
M. Msall., P.S. Monahan., N. Chapanis and M.L. Batshaw, Cognitive development in children with inborn errors of urea synthesis. Acta. Pediatr (Jpn). 30: 435–441 (1988).
J. Alberch., E. Perez-Navarro., N.E. Calvo and J. Marsal, Trophic factors protect neostriatal cholinergie neurons against quinolinic acid lesion, Soc. Neurosci. Abstr. 19: 276.12 (1993).
L. Ratnakumari., I.A. Qureshi and R.F. Butterworth, Loss of [3H]MK801 binding sites in brain in congenital ornithine transcarbamylase deficiency, Metabol Brain Dis. 10: 249–255 (1994).
F. Moroni, G. Lombardi, V. Carla, D. Pelligrini, G.L. Carassale and C. Cortesini, Content of quinolinic acid and other tryptophan metabolites increases in brains of rats used as experimental models of hepatic encephalopathy, J. Neurochem. 46:869–874 (1986).
V.L. Raghavendra Rao, A.K. Agrawal and Ch. R.K. Murthy, Ammonia-induced alteration in glutamate and muscimol binding to cerebellar synaptic membranes, Neurosci. Lett. 130:251–259 (1991).
J. Astrup, P. Sorensen and H. Sorensen, Oxygen and glucose consumption related to Na+-K+-transport in canine brain, Stroke. 12:726–730 (1981).
L. Ratnakumari, R. Audet, I.A. Qureshi and R.F. Butterworth, Na+,K+-ATPase activities are increased in brain in both congenital and aquired hyperammonemic syndromes, Neurosci. Lett. 197:89–92 (1995).
E. Kosenko, Y. Kaminsky, E. Gran, M.D. Minara, M.G. Grisolia, S. Grisolia and V. Felipo, Brain ATP depletion induced by acute ammonia intoxication in rats is mediated by activation of the NMDA receptor and Na+,K+-ATPase, J. Neurochem. 63:2172–2178 (1994).
. A.M. Bartello, A. Aperia, S.I. Walaas, A.C Nairn and P. Greengard, Phosphorylation of catalytic subunit of Na+- K+-ATPase inhibits the activity of the enzyme, Proc. Natl. Acad. Sci. USA. 88:11359–11362 (1991).
J.T. Neary, L-OB. Norenberg, M.P. Gutierrez and M.D. Norenberg, Hyperammonemia causes altered protein phosphorylation in astrocytes, Brain Res. 437:161–164 (1987).
N. Seiler, Is ammonia a pathogenetic factor in Alzheimers disease, Neurochem Res. 18:235–245 (1993).
S. Hoycr, Possible role of ammonia in the brain in dementia of Alzheimer type, in: Hepatic Encephalopathy and Hyperammonemia and Ammonia Toxicity, V. Felipo and S. Grisolia ed. Plenum Press, New York, pp 197–208 (1994).
F.M. Beal, Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses, Ann. Neurol. 31:119–130 (1992).
T. Gushiken, N. Yoshimura and T. Saheki, Transient hyperammonemia during aging in ornithine transcarbamylase-deficient, sparse-fur mice, Biochem. Int. 11:637–643 (1985).
C. Malo, I.A. Qureshi and J. Letarte, Postnatal maturation of enterocytes in sparse-fur mutant mice, Am. J. Physiol. 250:G177–184 (1986).
N. Seiler, C. Grauffel, G. Daune-Anglard, S. Sarhan and B. Knodgen, Decreased hyperammonemia and orotic aciduria due to inactivation of ornithine aminotransferase in mice with a hereditary abnormal ornithine carbamoyltransferase, J. Inher. Metab. Dis. 17:691–703 (1994).
K. Monastiri, D. Rabier and P. Kamoun, Prenatal diagnosis of ornithine transcarbamylase deficiency: Results in spfash mice, Prenatal Diagnosis. 13:441–447 (1993).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1997 Springer Science+Business Media New York
About this chapter
Cite this chapter
Qureshi, I.A., Rao, K.V.R. (1997). Sparse-Fur (spf) Mouse as a Model of Hyperammonemia: Alterations in the Neurotransmitter Systems. In: Felipo, V., Grisolía, S. (eds) Advances in Cirrhosis, Hyperammonemia, and Hepatic Encephalopathy. Advances in Experimental Medicine and Biology, vol 420. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5945-0_9
Download citation
DOI: https://doi.org/10.1007/978-1-4615-5945-0_9
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-7724-5
Online ISBN: 978-1-4615-5945-0
eBook Packages: Springer Book Archive