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Citations to this article

An arginine to glutamine mutation in residue 109 of human ornithine transcarbamylase completely abolishes enzymatic activity in Cos1 cells.
J T Lee, R L Nussbaum
J T Lee, R L Nussbaum
Published December 1, 1989
Citation Information: J Clin Invest. 1989;84(6):1762-1766. https://doi.org/10.1172/JCI114360.
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An arginine to glutamine mutation in residue 109 of human ornithine transcarbamylase completely abolishes enzymatic activity in Cos1 cells.

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Abstract

Ornithine transcarbamylase (OTC) is an important enzyme in the detoxification of ammonia to urea, and its deficiency is the most common inborn error of ureagenesis in humans. Among 24 cases of OTC deficiency previously examined, three unrelated individuals all showed loss of a Taq I site in the OTC gene corresponding to codon 109, suggesting that this Taq I site may be prone to mutation. Two of these patients demonstrated the same C----T transition (in antisense strand) converting Arg109 to Gln. Although these studies implied a strong association between the missense mutation and OTC-deficient phenotype, a causal relationship could not be firmly established. We have investigated this relationship by reconstructing the mutation in vitro. A full-length human OTC cDNA was cloned into an SV40-based expression vector and has been reproducibly expressed at high levels in the cell line Cos1. By site-directed mutagenesis of this wild type sequence, we constructed a missense mutation which contains the C----T transition. Electroporation and transient assay in Cos1 indicated that the specific activity of mutant OTC was 100-fold lower than that of wild type. This result confirms that the Taq I alteration leading to the Gln missense is responsible for the OTC deficiency affecting the above patients.

Authors

J T Lee, R L Nussbaum

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Citations to this article (33)

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Genetic variants in cardiac calcification in Northern Sweden:
U Hellman, S Mörner, M Henein
Medicine 2019
Neural-specific deletion of mitochondrial p32/C1qbp leads to leukoencephalopathy due to undifferentiated oligodendrocyte and axon degeneration
M Yagi, T Uchiumi, N Sagata, D Setoyama, R Amamoto, Y Matsushima, D Kang
Scientific Reports 2017
Cardiomyocyte-specific loss of mitochondrial p32/C1qbp causes cardiomyopathy and activates stress responses
T Saito, T Uchiumi, M Yagi, R Amamoto, D Setoyama, Y Matsushima, D Kang
Cardiovascular Research 2017
Klf15 Orchestrates Circadian Nitrogen Homeostasis
D Jeyaraj, FA Scheer, JA Ripperger, SM Haldar, Y Lu, DA Prosdocimo, SJ Eapen, BL Eapen, Y Cui, GH Mahabeleshwar, H Lee, MA Smith, G Casadesus, EM Mintz, H Sun, Y Wang, KM Ramsey, J Bass, SA Shea, U Albrecht, MK Jain
Cell Metabolism 2012
Thiol-Independent Action of Mitochondrial Thioredoxin To Support the Urea Cycle of Arginine Biosynthesis in Schizosaccharomyces pombe
JY Song, KD Kim, JH Roe
Eukaryotic cell 2008
Evidence for induction of the ornithine transcarbamylase expression in Alzheimer's disease
F Bensemain, D Hot, S Ferreira, J Dumont, S Bombois, CA Maurage, L Huot, X Hermant, E Levillain, C Hubans, F Hansmannel, J Chapuis, JJ Hauw, S Schraen, Y Lemoine, L Buée, C Berr, D Mann, F Pasquier, P Amouyel, JC Lambert
Molecular Psychiatry 2007
Long-Term Correction of Ammonia Metabolism and Prolonged Survival in Ornithine Transcarbamylase-Deficient Mice Following Liver-Directed Treatment with Adeno-associated Viral Vectors
D Moscioni, H Morizono, RJ McCarter, A Stern, J Cabrera-Luque, A Hoang, J Sanmiguel, D Wu, P Bell, GP Gao, SE Raper, JM Wilson, ML Batshaw
Molecular Therapy 2006
Differences in the Human and Mouse Amino-Terminal Leader Peptides of Ornithine Transcarbamylase Affect Mitochondrial Import and Efficacy of Adenoviral Vectors
X Ye, KP Zimmer, R Brown, C Pabin, ML Batshaw, JM Wilson, MB Robinson
Human Gene Therapy 2001
Genotype spectrum of ornithine transcarbamylase deficiency: Correlation with the clinical and biochemical phenotype
BA McCullough, M Yudkoff, ML Batshaw, JM Wilson, SE Raper, M Tuchman
American Journal of Medical Genetics 2000
Expression of Wild-Type and Mutant Human Ornithine Transcarbamylase Genes in Chinese Hamster Ovary Cells and Lack of Dominant Negative Effect of R141Q and R40H Mutants
L Augustin, M Mavinakere, H Morizono, M Tuchman
Pediatric Research 2000
Augmentation of urea-synthetic capacity by inhibition of nitric oxide synthesis in butyrate-induced differentiated human hepatocytes
JH Yoon, HS Lee, TH Kim, GH Woo, CY Kim
FEBS Letters 2000
Efficient mitochondrial import of newly synthesized ornithine transcarbamylase (OTC) and correction of secondary metabolic alterations in spf(ash) mice following gene therapy of OTC deficiency
KP Zimmer, M Bendiks, M Mori, E Kominami, MB Robinson, X Ye, JM Wilson
Molecular Medicine 1999
Correction of Ureagenesis after Gene Transfer in an Animal Model and after Liver Transplantation in Humans with Ornithine Transcarbamylase Deficiency
ML Batshaw, MB Robinson, X Ye, C Pabin, Y Daikhin, BK Burton, JM Wilson, M Yudkoff
Pediatric Research 1999
Efficient Mitochondrial Import of Newly Synthesized Ornithine Transcarbamylase (OTC) and Correction of Secondary Metabolic Alterations in spfash Mice following Gene Therapy of OTC Deficiency
KP Zimmer, M Bendiks, M Mori, E Kominami, MB Robinson, X Ye, JM Wilson
Molecular Medicine 1999
Adenovirus-Mediated in Vivo Gene Transfer Rapidly Protects Ornithine Transcarbamylase-Deficient Mice from an Ammonium Challenge
X Ye, MB Robinson, C Pabin, T Quinn, A Jawad, JM Wilson, ML Batshaw
Pediatric Research 1997
Familial lethal inheritance of a mutated paternal gene in females causing X-linked ornithine transcarbamylase (OTC) deficiency
S Komaki, T Matsuura, K Oyanagi, R Hoshide, K Kiwaki, F Endo, M Shimadzu, I Matsuda
American Journal of Medical Genetics 1997
Partial duplication [dup. TCAC (178)] and novel point mutations (T125M, G188R, A209V, and H302L) of the ornithine transcarbamylase gene in congenital hyperammonemia
B Gilbert-Dussardier, B Segues, JM Rozet, D Rabier, P Calvas, L Lumley, JP Bonnefond, A Munnich
Human Mutation 1996
Clinical and biochemical heterogeneity in females of a large pedigree with ornithine transcarbamylase deficiency due to the R141Q mutation
MJ Ahrens, SA Berry, CB Whitley, DJ Markowitz, RJ Plante, M Tuchman
American Journal of Medical Genetics 1996
Prolonged Metabolic Correction in Adult Ornithine Transcarbamylase-deficient Mice with Adenoviral Vectors
X Ye, MB Robinson, ML Batshaw, EE Furth, I Smith, JM Wilson
The Journal of biological chemistry 1996
Mutations and polymorphisms in the human ornithine transcarbamylase gene: Mutation update addendum
M Tuchman, RJ Plante
Human Mutation 1995
Identification of two new aberrant splicings in the ornithine carbamoyltransferase (OCT) gene in two patients with early and late onset OCT deficiency
T Matsuura, R Hoshide, S Komaki, K Kiwaki, F Endo, S Nakamura, T Jitosho, I Matsuda
Journal of Inherited Metabolic Disease 1995
Expression of four mutant human ornithine transcarbamylase genes in cultured Cos 1 cells relates to clinical phenotypes
T Matsuura, R Hoshide, C Setoyama, S Komaki, K Kiwaki, F Endo, S Nishikawa, I Matsuda
Human Genetics 1994
Hyperammoniemic coma in an adolescent girl: An unusual case of ornithine transcarbamylase deficiency
M Perini, D Zarcone, C Corbetta
The Italian Journal of Neurological Sciences 1993
Mutations and polymorphisms in the human ornithine transcarbamylase gene
M Tuchman
Human Mutation 1993
Site specific screening for point mutations in ornithine transcarbamylase deficiency
D Feldmann, JM Rozet, A Pelet, D Hentzen, P Briand, P Hubert, C Largilliere, D Rabier, JP Farriaux, A Munnich
Journal of medical genetics 1992
Screening for gene deletions and known mutations in 13 patients with ornithine transcarbamylase deficiency
PJ Suess, MY Tsai, RA Holzknecht, M Horowitz, M Tuchman
Biochemical Medicine and Metabolic Biology 1992
Improved molecular diagnostics for ornithine transcarbamylase deficiency
M Grompe, CT Caskey, RG Fenwick
The American Journal of Human Genetics 1991
Retrospective survey of urea cycle disorders: Part 1. Clinical and laboratory observations of thirty-two Japanese male patients with ornithine transcarbamylase deficiency
I Matsuda, N Nagata, T Matsuura, K Oyanagi, K Tada, K Narisawa, T Kitagawa, T Sakiyama, F Yamashita, M Yoshino
American Journal of Medical Genetics 1991
Arginine 109 to glutamine mutation in a girl with ornithine carbamoyl transferase deficiency
S Strautnieks, P Rutland, S Malcolm
Journal of medical genetics 1991
Fatal hyperammonemia resulting from a C-to-T mutation at a MspI site of the ornithine transcarbamylase gene
D Hentzen, A Pelet, D Feldman, D Rabier, J Berthelot, A Munnich
Human Genetics 1991
Two different point G to A mutations in exon 10 of the porphobilinogen deaminase gene are responsible for acute intermittent porphyria
MH Delfau, C Picat, FW de Rooij, K Hamer, M Bogard, JH Wilson, JC Deybach, Y Nordmann, B Grandchamp
Journal of Clinical Investigation 1990

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