Structural organization of the human carbamyl phosphate synthetase I gene (CPS1) and identification of two novel genetic lesions

Funghini, Silvia; Donati, Maria Alice; Pasquini, Elisabetta; Zammarchi, Enrico; Morrone, Amelia

doi:10.1002/humu.9184

Cited by 23 publications

(24 citation statements)

References 14 publications

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“…Enzyme activity and mutation analysis are necessary for a correct diagnosis [31]. However, due to the large size of the gene located on chromosome 2, and the heterogeneity of the mutant alleles, functional characterization of mutations may be necessary to determine causality [32][33][34].…”

Section: Carbamyl Phosphate Synthetase Imentioning

confidence: 99%

Contrasting features of urea cycle disorders in human patients and knockout mouse models

Deignan

Cederbaum

Grody

2008

Molecular Genetics and Metabolism

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The urea cycle exists for the removal of excess nitrogen from the body. Six separate enzymes comprise the urea cycle, and a deficiency in any one of them causes a urea cycle disorder (UCD) in humans. Arginase is the only urea cycle enzyme with an alternate isoform, though no known human disorder currently exists due to a deficiency in the second isoform. While all of the UCDs usually present with hyperammonemia in the first few days to months of life, most disorders are distinguished by a characteristic profile of plasma amino acid alterations that can be utilized for diagnosis. While enzyme assay is possible, an analysis of the underlying mutation is preferable for an accurate diagnosis. Mouse models for each of the urea cycle disorders exist (with the exception of NAGS deficiency), and for almost all of them, their clinical and biochemical phenotypes rather closely resemble the phenotypes seen in human patients. Consequently, all of the current mouse models are highly useful for future research into novel pharmacological and dietary treatments and gene therapy protocols for the management of urea cycle disorders.

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Section: Carbamyl Phosphate Synthetase Imentioning

confidence: 99%

Contrasting features of urea cycle disorders in human patients and knockout mouse models

Deignan

Cederbaum

Grody

2008

Molecular Genetics and Metabolism

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“…introns [4][5][6], with 4,500 coding nucleotides, encodes a 1500-residue proenzyme [7] that is synthesized in hepatocytes and enterocytes [8,9], and which, upon internalization to the mitochondrial matrix, yields after cleavage of its N-terminal 38 amino acids, the mature 1,462-amino acid multidomain (Fig. 1A) CPS1 protein [10][11][12] [E.C.…”

Section: Introductionmentioning

confidence: 99%

Understanding carbamoyl phosphate synthetase (CPS1) deficiency by using the recombinantly purified human enzyme: Effects of CPS1 mutations that concentrate in a central domain of unknown function

Dı́ez-Fernández

Cervera

et al. 2014

Molecular Genetics and Metabolism

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Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is an inborn error of the urea cycle that is due to mutations in the CPS1 gene. In the first large repertory of mutations found in CPS1D, a small CPS1 domain of unknown function (called the UFSD) was found to host missense changes with high frequency, despite the fact that this domain does not host substrate-binding or catalytic machinery. We investigate here by in vitro expression studies using baculovirus/insect cells the reasons for the prominence of the UFSD in CPS1D, as well as the disease-causing roles and pathogenic mechanisms of the mutations affecting this domain. All but three of the 18 missense changes found thus far mapping in this domain in CPS1D patients drastically decreased the yield of pure CPS1, mainly because of decreased enzyme solubility, strongly suggesting misfolding as a major determinant of the mutations negative effects. In addition, the majority of the mutations also decreased from modestly to very drastically the specific activity of the fraction of the enzyme that remained soluble and that could be purified, apparently because they decreased V max . Substantial although not dramatic increases in K m values for the substrates or for N-acetyl-L-glutamate were observed for only five mutations.Similarly, important thermal stability decreases were observed for three mutations. The results indicate a disease-causing role for all the mutations, due in most cases to the combined effects of the low enzyme level and the decreased activity. Our data strongly support the value of the present expression system for ascertaining the disease-causing potential of CPS1 mutations, provided that the CPS1 yield is monitored. The observed effects of the mutations have been rationalized on the basis of an existing structural model of CPS1. This model shows that the UFSD, which is in the middle of the 1462-residue multidomain CPS1 protein, plays a key integrating role for creating the CPS1 multidomain architecture leading us to propose here a denomination of "Integrating 3 Domain" for this CPS1 region. The majority of these 18 mutations distort the interaction of this domain with other CPS1 domains, in many cases by causing improper folding of structural elements of the Integrating Domain that play key roles in these interactions.

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“…The CPS1 gene spans approximately 122 kb on chromosome 2q35 and consists of 38 exons (Hoshide et al 1995;Summar 1998;Summar et al 1995Summar et al , 2003Haraguchi et al 1991). Because of the large size of the gene, mutational analyses of affected individuals have been reported for only 33 cases worldwide (Summar 1998;Hä berle and Koch 2004;Hä berle et al 2003;Rapp et al 2001;Finckh et al 1998;Funghini et al 2003), fewer in Japan (Wakutani et al 2004;Aoshima et al 2001a, b;Hoshide et al 1993;Ihara 1999), and without a known common mutation, molecular diagnosis has been unavailable for most affected families. Thirdly, the clinical diagnostic criteria of CPS1D, i.e., hyperammonemia associated with low/absent serum citrulline and urinary orotic acid excretion, cannot discriminate CPS1D from another disorder, N-acetylglutamate synthetase (NAGS) deficiency.…”

Section: Introductionmentioning

confidence: 99%

Molecular and clinical analyses of Japanese patients with carbamoylphosphate synthetase 1 (CPS1) deficiency

et al. 2007

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Carbamoylphosphate synthetase I deficiency (CPS1D) is a urea-cycle disorder characterized by episodes of life-threatening hyperammonemia. Correct diagnosis is crucial for patient management, but is difficult to make from clinical presentation and conventional laboratory tests alone. Enzymatic or genetic diagnoses have also been hampered by difficult access to the appropriate organ and the large size of the gene (38 exons). In this study, in order to address this diagnostic dilemma, we performed the largest 349-354 DOI 10.1007/s10038-007-0122-9 mutational and clinical analyses of this disorder to date in Japan. Mutations in CPS1 were identified in 16 of 18 patients with a clinical diagnosis of CPS1D. In total, 25 different mutations were identified, of which 19 were novel. Interestingly, in contrast to previous reports suggesting an extremely diverse mutational spectrum, 31.8% of the mutations identified in Japanese were common to more than one family. We also identified two common polymorphisms that might be useful for simple linkage analysis in prenatal diagnosis. The accumulated clinical data will also help to reveal the clinical presentation of this rare disorder in Japan.

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Structural organization of the human carbamyl phosphate synthetase I gene (CPS1) and identification of two novel genetic lesions

Cited by 23 publications

References 14 publications

Contrasting features of urea cycle disorders in human patients and knockout mouse models

Contrasting features of urea cycle disorders in human patients and knockout mouse models

Understanding carbamoyl phosphate synthetase (CPS1) deficiency by using the recombinantly purified human enzyme: Effects of CPS1 mutations that concentrate in a central domain of unknown function

Molecular and clinical analyses of Japanese patients with carbamoylphosphate synthetase 1 (CPS1) deficiency

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