Abstract
Citrullinemia (OMIM 215700) (McKusick, 1998) is an autosomal recessive disease that is caused by a deficiency of argininosuccinate synthetase (ASS; EC 6.3.4.5). The clinical, biochemical and molecular aspects of citrullinemia have been reviewed elsewhere (Walser, 1983; Saheki et al., 1987a; McKusick, 1998). So far, we have analyzed almost 200 patients with citrullinemia in our laboratory and have classified them into three types according to enzyme abnormality and into two forms according to pathogenesis (Figure 1) (Saheki et al., 1981, 1985a, 1987a, b; Kobayashi et al., 1993, 1999). The first form is the classical form (CTLN1) found in most patients with neonatal/infantile-onset citrullinemia (type I and type III), first described by (1962); the second form is the adult-onset type II citrullinemia (CTLN2) caused by a liver-specific ASS deficiency. In CTLN1, the enzyme defect is found in all tissues and cells in which ASS is expressed (Saheki et al., 1980, 1981, 1982, 1983a, 1985a, b, 1987a, b). To date, we have identified 36 mutations in the ASS gene located on chromosome 9q34 and have clarified the pathogenesis of most CTLN1 patients at the molecular level (Kobayashi et al., 1987, 1990, 1991, 1994, 1995a; Kakinoki et al., 1997).
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Bradford, N.M. and McGivan, J.D., 1980, Evidence for the existence of an ornithine/citrulline antiporter in rat liver mitochondria, FEBS Lett. 113, 294–298.
Camacho, J.A., Obie, C., Biery, B., Goodman, B.K., Hu, C.-A., Almashanu, S., Steel, G., Casey, R., Lambert, M., Mitchell, G.A. and Valle, D., 1999, Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter, Nature Genet. 22, 151–158.
Cheung, C.-W., Cohen, N.S. and Raijman, L., 1989, Channeling of urea cycle intermediates in situ in permeabilized hepatocytes, J. Biol. Chem. 264, 4038–4044.
Chow, W.C., Ng, H.S., Tan, I.K. and Thum, T.Y., 1996, Case report: Recurrent hyperam-monaemic encephalopathy due to citrullinaemia in a 52 year old man, J. Gastroenterol. Hepatol. 11, 621–625.
Crackower, M.A., Sinasac, D.S., Lee, J.R., Herbrick, J.-A., Tsui, L.-C. and Scherer, S.W., 1999, Assignment of the SLC25A12 gene coding for the human calcium-binding mitochondrial solute carrier protein aralar to human chromosome 2q24, Cytogenet. Cell Genet. 87, 197–198.
de Jonge, W.J., Dingemanse, M.A., de Boer, P.A.J., Lamers, W.H. and Moorman, A.F.M., 1998, Arginine-metabolizing enzymes in the developing rat small intestine, Pediatr Res. 43, 442–451.
del Arco, A. and Satrústcgui, J., 1998, Molecular cloning of aralar, a new member of the mitochondrial carrier superfamily that binds calcium and is present in human muscle and brain, J. Biol. Chem. 273, 23327–23334.
del Arco, A., Agudo, M. and Satrústegui, J., 2000, Characterization of a second member of the subfamily of calcium-binding mitochondrial carriers expressed in human non-excitable tissues, Biochem J. 345, 725–732.
Demarquoy, J., Fairand, A., Gautier, C. and Vaillant, R., 1994, Demonstration of argininosuccinate synthetase activity associated with mitochondrial membrane: Characterization and hormonal regulation, Mol. Cell Biochem. 136, 145–155.
Funahashi, M., Kato, H., Shiosaka, S. and Nakagawa, H., 1981, Formation of arginine and guanidinoacetic acid in the kidney in vivo: Their relations with the liver and their regulation, J. Biochem. 89, 1347–1356.
Gamble, J.G. and Lehninger, A.L., 1973, Transport of ornithine and citrulline across the mitochondrial membrane, J. Biol. Chem. 248, 610–618.
Gunter, TE., Gunter, K.K., Sheu, S.-S. and Gavin, C.E., 1994, Mitochondrial calcium transport: Physiological and pathological relevance, Am. J. Physiol. 267, C313–C339.
Häusinger, D., 1990, Nitrogen metabolism in liver: Structural and functional organization and physiological relevance, Biochem. J. 267, 281–290.
Imamura, Y., Kobayashi, K., Yamashita, T, Saheki, T, Ichiki, H., Hashida, S. and Ishikawa, E., 1987, Clinical application of enzyme immunoassay in the analysis of citrullinemia, Clin. Chim. Acta 164, 201–208.
Indiveri, C., Tonazzi, A., Stipani, I. and Palmieri, F., 1997, The purified and reconstituted ornithine/citrulline carrier from rat liver mitochondria: Electrical nature and coupling of the exchange reaction with H+ translocation, Biochem. J. 327, 349–356.
Inose, T, 1952, Hepatocerebral degeneration, a special type, J. Neuropath. Exp. Neurol. 11, 401–408.
Inoue, I., Saheki, T, Kayanuma, K., Uono, M., Nakajima, M., Takeshita, K., Koike, R., Yuasa, T., Miyatake, T. and Sakoda, K., 1988, Biochemical analysis of decreased ornithine transport activity in the liver mitochondria from patients with hyperornithinemia, hyperammonemia and homocitrullinuria, Biochim. Biophys. Acta 964, 90–95.
Isayama, H., Nakamura, H., Kanemaru, H., Kobayashi, K., Emson, P.C., Kawabuchi, M. and Tashiro, N., 1997, Distribution and co-localization of nitric oxide synthase and argininosuccinate synthetase in the cat hypothalamus, Arch. Histol. Cytol. 60, 477–492.
Kakinoki, H., Kobayashi, K., Terazono, H., Nagata, Y. and Saheki, T., 1997, Mutations and DNA diagnoses of classical citrullinemia, Hum. Mutat. 9, 250–259.
Kawamoto, S., Strong, R.W., Kerlin, P., Lynch, S.V., Steadman, C., Kobayashi, K., Nakagawa, S., Matsunami, H., Akatsu, T. and Saheki, T., 1997, Orthotopic liver transplantation for adult-onset type II citrullinemia, Clin. Transplantation 11, 453–458.
Kawasaki, H. and Kretsinger, R.H., 1994, Calcium-binding proteins, Protein Profile 1, 343–517.
Kobayashi, K., Saheki, T., Imamura, Y., Noda, T., Inoue, I., Matuo, S., Hagihara, S., Nomiyama, H., Jinno, Y. and Shimada, K., 1986, Messenger RNA coding for argininosuccinate synthetase in citrullinemia, Am. J. Hum. Genet. 38, 667–680.
Kobayashi, K, Ichiki, H., Saheki, T., Tatsuno, M., Uchiyama, C., Nukada, O. and Yoda, T., 1987, Structure of an abnormal messenger RNA for argininosuccinate synthetase in citrullinemia, Hum. Genet. 76, 27–32.
Kobayashi, K., Jackson, M.J., Tick, D.B., O’Brien, W.E. and Beaudet, A.L., 1990, Heterogeneity of mutations in argininosuccinate synthetase causing human citrullinemia, J. Biol. Chem. 265, 11361–11367.
Kobayashi, K., Rosenbloom, C., Beaudet, A.L. and O’Brien, W.E., 1991, Additional mutations in argininosuccinate synthetase causing citrullinemia, Mol. Biol. Med. 8, 95–100.
Kobayashi, K, Shaheen, N., Kumashiro, R., Tanikawa, K., O’Brien, W.E., Beaudet, A.L. and Saheki, T, 1993, A search for the primary abnormality in adult-onset type II citrullinemia, Am. J. Hum. Genet. 53, 1024–1030.
Kobayashi, K., Shaheen, N., Terazono, H. and Saheki, T, 1994, Mutations in argininosuccinate synthetase mRNA of Japanese patients, causing classical citrullinemia, Am. J. Hum. Genet. 55, 1103–1112.
Kobayashi, K, Kakinoki, H., Fukushige, T, Shaheen, N., Terazono, H. and Saheki, T, 1995a, Nature and frequency of mutations in the argininosuccinate synthetase gene that cause classical citrullinemia, Hum. Genet. 96, 454–463.
Kobayashi, K., Nakata, M., Terazono, H., Shinsato, T. and Saheki, T, 1995b, Pancreatic secretory trypsin inhibitor gene is highly expressed in the liver of adult-onset type II citrullinemia, FEBS Lett. 372, 69–73.
Kobayashi, K., Horiuchi, M. and Saheki, T, 1997, Pancreatic secretory trypsin inhibitor as a diagnostic marker for adult-onset type II citrullinemia, Hepatology 25, 1160–1165.
Kobayashi, K, Sinasac, D.S., Iijima, M., Boright, A.P., Begum, L., Lee, J.R., Yasuda, T, Ikeda, S., Hirano, R., Terazono, H., Crackower, M.A., Kondo, I., Tsui, L.-C., Scherer, S.W. and Saheki, T., 1999, The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein, Nature Genet. 22, 159–163.
Li, M.X., Nakajima, T, Fukushige, T, Kobayashi, K., Seiler, N. and Saheki, T, 1999, Aberrations of ammonia metabolism in ornithine carbamoyltransferase-deficienct spf-ash mice and their prevention by treatment with urea cycle intermediate amino acids and an ornithine aminotransferase inactivator, Biochim. Biophys. Acta 1455, 1–11.
McKusick, V.A., 1998, Citrullinemia, in Mendelian Inheritance in Man, Vol. 3, V.A. McKusick (ed.), Johns Hopkins University Press, Baltimore, pp. 2093–2095.
McMurray, W.C., Mohyuddin, F., Rossiter, R.J., Rathbun, J.C., Valentine, G.H., Koegler, S.J. and Zarfas, D.E., 1962, Citrullinuria: A new aminoaciduria associated with mental retardation, Lancet 1, 138.
Miyakoshi, T, Takahashi, T., Kato, M., Watanabe, M. and Ito, C, 1968, Abnormal citrulline metabolism of Inose-type hepatocerebral disease, Shinkeikagaku (Japanese) 7, 88–91.
Nakagawa, S., Mizuma, M., Ichiki, H. and Saheki, T, 1991, Immunocytochemical demonstration of argininosuccinate synthetase in the neuronal structures of the intestinal tract and pancreas of the Japanese monkey, Acta Histochem. Cytochem. 24, 209–213.
Nakata, M., Yada, T., Nakagawa, S., Kobayashi, K. and Maruyama, I., 1997, Citrulline-argininosuccinate-arginine cycle coupled to Ca2+-signaling in rat pancreatic β-cells, Biochem. Biophys. Res. Commun. 235, 619–624.
Palmieri, L., de Marco, V., Iacobazzi, V., Palmieri, F., Runswick, M.J. and Walker, J.E., 1997, Identification of the yeast ARG-11 gene as a mitochondrial ornithine carrier involved in arginine biosynthesis, FEBS Lett. 410, 447–451.
Roerdink, RH., Gouw, W.L.M., Okken, A., Van der Blij, J.F., Haan, G.L., Hommes, RA. and Huisjes, H.J., 1973, Citrullinemia, report of a case, with studies on antenatal diagnosis, Pediatr. Res. 7, 863–869.
Saheki, T., Tsuda, M., Takada, S., Kusumi, K. and Katsunuma, T., 1980, Role of argininosuccinate synthetase in the regulation of urea synthesis in the rat and argininosuccinate synthetase-associated metabolic disorder in man, Adv. Enzyme Regulation 18, 221–238.
Saheki, T., Ueda, A., Hosoya, M., Kusumi, K., Takada, S., Tsuda, M. and Katsunuma, T, 1981, Qualitative and quantitative abnormalities of argininosuccinate synthetase in citrullinemia, Clin. Chim. Acta 109, 325–335.
Saheki, T., Ueda, A., Iizima, K., Yamada, N., Kobayashi, K., Takahashi, K. and Katsunuma, T., 1982, Argininosuccinate synthetase activity in cultured skin fibroblasts of citrullinemic patients, Clin. Chim. Acta 118, 93–97.
Saheki, T., Ueda, A., Hosoya, M., Sase, M., Nakano, K. and Katsunuma, T., 1983a, Enzymatic analysis of citrullinemia (12 cases) in Japan, Adv. Exp. Med. Biol. 153, 63–76.
Saheki, T, Yagi, Y, Sase, M., Nakano, K. and Sato, E., 1983b, Immunohistochemical localization of argininosuccinate synthetase in the liver of control and citrullinemic patients, Biomed. Res. 4, 235–238.
Saheki, T., Nakano, K., Kobayashi, K., Imamura, Y, Itakura, Y, Sase, M., Hagihara, S. and Matuo, S., 1985a, Analysis of the enzyme abnormality in eight cases of neonatal and infantile citrullinemia in Japan, J. Inherit. Metab. Dis. 8, 155–156.
Saheki, T, Sase, M., Nakano, K. and Yagi, Y, 1985b, Arginine metabolism in citrullinemic patients, in Guanidines, A. Mori, B.D. Cohen and A. Lowenthal (eds.), Plenum, New York, pp. 149–158.
Saheki, T., Kobayashi, K., Miura, T., Hashimoto, S., Ueno, Y., Yamasaki, T., Araki, H., Nara, H., Shiozaki, Y, Sameshima, Y, Suzuki, M., Yamauchi, Y, Sakazume, Y, Akiyama, K. and Yamamura, Y, 1986, Serum amino acid pattern of type II citrullinemic patients and effect of oral administration of citrulline, J. Clin. Biochem. Nutr. 1, 129–142.
Saheki, T., Kobayashi, K. and Inoue, I., 1987a, Hereditary disorders of the urea cycle in man: Biochemical and molecular approaches, Rev. Physiol. Biochem. Pharmacol. 108, 21–68.
Saheki, T., Kobayashi, K., Ichiki, H., Matuo, S., Tatsuno, M., Imamura, Y, Inoue, I., Noda, T. and Hagihara, S., 1987b, Molecular basis of enzyme abnormalities in urea cycle disorders: With special reference to citrullinemia and argininosuccinic aciduria, Enzyme 38, 227–232.
Saheki, T., Kobayashi, K., Inoue, I., Matuo, S., Hagihara, S. and Noda, T., 1987c, Increased urinary excretion of argininosuccinate in type II citrullinemia, Clin. Chim. Acta 170, 297–304.
Sase, M., Kobayashi, K, Imamura, Y, Saheki, T, Nakano, K., Miura, S. and Mori, M., 1985, Level of translatable messenger RNA coding for argininosuccinate synthetase in the liver of the patients with quantitative-type citrullinemia, Hum. Genet. 69, 130–134.
Sinasac, D.S., Crackower, M.A., Lee, J.R., Kobayashi, K., Saheki, T., Scherer, S.W. and Tsui, L.-C, 1999, Genomic structure of the adult-onset type II citrullinemia gene, SLC25A13, and cloning and expression of its mouse homologue, Genomics 62, 289–292.
Todo, S., Starzl, T.E., Tzakis, A., Benkov, K.J., Kalousek, R., Saheki, T., Tanikawa, K. and Fenton, W.A., 1992, Orthotopic liver transplantation for urea cycle enzyme deficiency, Hepatology 15, 419–422.
Tsujii, T., Morita, T., Matsuyama, Y, Matsui, T., Tamura, M. and Matsuoka, Y, 1976, Sibling cases of chronic recurrent hepatocerebral disease with hypercitrullinemia, Gastroenterologia Japonica 11, 328–340.
Vidailhet, M., Levin, B., Dautrevaux, M., Paysant, P., Gelot, S., Badonnel, Y., Pierson, M. and Neimann, N, 1971, Citrullinemie, Arch. France Ped. 28, 521–532.
Vito, P., Lacana, E. and D’Adamio, L., 1996, Interfering with apoptosis: Ca2+-binding protein ALG-2 and Alzheimer’s disease gene ALG-3, Science 271, 521–525.
Walker, J.E., 1992, The mitochondrial transporter family, Curr. Opin. Struct. Biol. 2, 519–526.
Walser, M., 1983, Urea cycle disorders and other hereditary hyperammonemic syndrome, in The Metabolic Basis of Inherited Disease, J.B. Stanbury, J.B. Wyngaarden, D.S. Frederikson, J.L. Goldstein and M.S. Brown (eds.), McGraw-Hill, New York, pp. 402–438.
Weber, F.E., Minestrini, G., Dyer, J.H., Werder, M., Boffelli, D., Compassi, S., Wehrli, E., Thomas, R.M., Schulthess, G. and Hauser, H., 1997, Molecular cloning of a peroxisomal Ca2+-dependent member of the mitochondrial carrier superfamily, Proc. Natl. Acad. Sci. USA 94, 8509–8514.
Windmueller, H.G. and Spaeth, A.E., 1981, Source and fate of circulating citrulline, Am. J. Physiol. 241, E473–E480.
Yagi, Y., Saheki, T., Imamura, Y., Kobayashi, K., Sase, M., Nakano, K., Matuo, S., Inoue, I., Hagihara, S., and Noda, T., 1988, The heterogeneous distribution of argininosuccinate synthetase in the liver of type II citrullinemic patients: Its specificity and possible clinical implications, Am. J. Clin. Pathol. 89, 735–741.
Yajima, Y., Hirasawa, T. and Saheki, T, 1982, Diurnal fluctuation of blood ammonia levels in adult-type citrullinemia, Tohoku J. Exp. Med. 137, 213–220.
Yazaki, M., Ikeda, S., Takei, Y., Yanagisawa, N., Matsunami, H., Hashikura, Y, Kawasaki, S., Makuuchi, M., Kobayashi, K. and Saheki, T., 1996, Complete neurological recovery of an adult patient with type II citrullinaemia after living related partial liver transplantation, Transplantation 62, 1679–1681.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2000 Springer Science+Business Media New York
About this chapter
Cite this chapter
Kobayashi, K. et al. (2000). Type II Citrullinemia (Citrin Deficiency): A Mysterious Disease caused by a Defect of Calcium-Binding Mitochondrial Carrier Protein. In: Pochet, R., Donato, R., Haiech, J., Heizmann, C., Gerke, V. (eds) Calcium: The Molecular Basis of Calcium Action in Biology and Medicine. Springer, Dordrecht. https://doi.org/10.1007/978-94-010-0688-0_33
Download citation
DOI: https://doi.org/10.1007/978-94-010-0688-0_33
Publisher Name: Springer, Dordrecht
Print ISBN: 978-0-7923-6422-1
Online ISBN: 978-94-010-0688-0
eBook Packages: Springer Book Archive