Mice deficient in the urea‐cycle enzyme, carbamoyl phosphate synthetase i, die during the early neonatal period from hyperammonemia

Ammonia liberated during amino acid catabolism in mammals is highly neurotoxic and is detoxified by the five enzymes of the urea cycle that are expressed within the liver. Inborn errors of each of the urea cycle enzymes occur in humans. Carbamoyl phosphate synthetase I (CPSase I; EC 6.3.4.16) is loc...

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Veröffentlicht in:Hepatology (Baltimore, Md.) Md.), 1999-01, Vol.29 (1), p.181-185
Hauptverfasser: Schofield, J. Paul, Cox, Timothy M., Caskey, C. Thomas, Wakamiya, Maki
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container_title Hepatology (Baltimore, Md.)
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creator Schofield, J. Paul
Schofield, J. Paul
Cox, Timothy M.
Caskey, C. Thomas
Wakamiya, Maki
description Ammonia liberated during amino acid catabolism in mammals is highly neurotoxic and is detoxified by the five enzymes of the urea cycle that are expressed within the liver. Inborn errors of each of the urea cycle enzymes occur in humans. Carbamoyl phosphate synthetase I (CPSase I; EC 6.3.4.16) is located within the inner mitochondrial matrix and catalyzes the initial rate‐limiting step of the urea cycle. Unless treated, complete deficiency of CPSase I, a rare autosomal recessive disease, causes death in newborn infants. Survivors are often mentally retarded and suffer frequent hyperammonemic crises during intercurrent illness or other catabolic stresses. Biochemically, CPSase I deficiency is characterized by high levels of blood ammonia, glutamine, and alanine, with low or absent citrulline and arginine levels. As a first step toward the development of gene therapy directed to the hepatocyte, we have generated a CPSase I–deficient mouse by gene targeting. Mice with homozygous disruption of CPSase I (CPSase [−/−] mice) die within 36 hours of birth with overwhelming hyperammonemia, and without significant liver pathology. This animal is a good model of human CPSase I deficiency.
doi_str_mv 10.1002/hep.510290112
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Paul</creatorcontrib><creatorcontrib>Schofield, J. Paul</creatorcontrib><creatorcontrib>Cox, Timothy M.</creatorcontrib><creatorcontrib>Caskey, C. Thomas</creatorcontrib><creatorcontrib>Wakamiya, Maki</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Hepatology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schofield, J. Paul</au><au>Schofield, J. Paul</au><au>Cox, Timothy M.</au><au>Caskey, C. Thomas</au><au>Wakamiya, Maki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mice deficient in the urea‐cycle enzyme, carbamoyl phosphate synthetase i, die during the early neonatal period from hyperammonemia</atitle><jtitle>Hepatology (Baltimore, Md.)</jtitle><addtitle>Hepatology</addtitle><date>1999-01</date><risdate>1999</risdate><volume>29</volume><issue>1</issue><spage>181</spage><epage>185</epage><pages>181-185</pages><issn>0270-9139</issn><eissn>1527-3350</eissn><coden>HPTLD9</coden><abstract>Ammonia liberated during amino acid catabolism in mammals is highly neurotoxic and is detoxified by the five enzymes of the urea cycle that are expressed within the liver. Inborn errors of each of the urea cycle enzymes occur in humans. Carbamoyl phosphate synthetase I (CPSase I; EC 6.3.4.16) is located within the inner mitochondrial matrix and catalyzes the initial rate‐limiting step of the urea cycle. Unless treated, complete deficiency of CPSase I, a rare autosomal recessive disease, causes death in newborn infants. Survivors are often mentally retarded and suffer frequent hyperammonemic crises during intercurrent illness or other catabolic stresses. Biochemically, CPSase I deficiency is characterized by high levels of blood ammonia, glutamine, and alanine, with low or absent citrulline and arginine levels. As a first step toward the development of gene therapy directed to the hepatocyte, we have generated a CPSase I–deficient mouse by gene targeting. Mice with homozygous disruption of CPSase I (CPSase [−/−] mice) die within 36 hours of birth with overwhelming hyperammonemia, and without significant liver pathology. This animal is a good model of human CPSase I deficiency.</abstract><cop>Philadelphia, PA</cop><pub>W.B. Saunders</pub><pmid>9862865</pmid><doi>10.1002/hep.510290112</doi><tpages>5</tpages></addata></record>
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source Wiley Online Library - AutoHoldings Journals; MEDLINE; EZB Electronic Journals Library
subjects Amino Acid Sequence
Ammonia - blood
Animals
Animals, Newborn
Base Sequence
Biological and medical sciences
Brain - enzymology
Carbamoyl-Phosphate Synthase (Ammonia) - deficiency
Carbamoyl-Phosphate Synthase (Ammonia) - genetics
Disease Models, Animal
Errors of metabolism
Gene Targeting
Genetic Vectors
Genotype
Liver - enzymology
Medical sciences
Metabolic diseases
Mice
Mice, Mutant Strains
Miscellaneous hereditary metabolic disorders
Molecular Sequence Data
Urea - metabolism
title Mice deficient in the urea‐cycle enzyme, carbamoyl phosphate synthetase i, die during the early neonatal period from hyperammonemia
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