The frequent observation of evidence for nonsense-mediated decay in RNA from patients with carbamyl phosphate synthetase I deficiency

Eeds, Angela; Hall, Lynn; Yadav, Meeta; Willis, Alecia; Summar, Samantha R.; Putnam, A; Barr, Frederick E.; Summar, Marshall

doi:10.1016/j.ymgme.2006.04.006

Cited by 16 publications

(26 citation statements)

References 17 publications

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“…We suggest that p.A704 V mutation might produce new marks in the transcript, which could be detected by a mechanism inducing mRNA degradation. This observation is consistent with previous results by Eeds et al [2006], who reported two patients carrying carbamyl phosphate synthetase I (CPSI) missense mutations that elicited decay. In that study, the authors concluded that the two CPSI mutations might affect splicing through disruption of exon splicing enhancers and subsequently to result in mRNA degradation.…”

Section: Discussionsupporting

confidence: 93%

“…Furthermore, NMD is a critical process for normal cellular development [Frischmeyer and Dietz, 1999;Mendell et al, 2004]. Reductions in the level of mutant mRNA transcripts have been associated with PTC mutations in the breast cancer 1 [Perrin-Vidoz et al, 2002], DNA polymerase gamma [Chan et al, 2005], carbamyl phosphate synthetase I [Eeds et al, 2006], iduronate 2-sulfatase [Lualdi et al, 2006], and acid beta-glucosidase [Montfort et al, 2006] genes. An experimentally defined rule in NMD indicates that PTCs occurring 50 to 55 nucleotides upstream of the 3 0 most exon-exon junction, mediate a reduction in mRNA abundance [Cheng et al, 1994;Nagy and Maquat, 1998;Zhang et al, 1998].…”

Section: Introductionmentioning

confidence: 99%

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Expression of the muscle glycogen phosphorylase gene in patients with McArdle disease: the role of nonsense-mediated mRNA decay

et al. 2008

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Nearly 35% of all mutations identified in the muscle glycogen phosphorylase gene (PYGM) in patients with McArdle disease result in premature termination codons (PTCs), particularly the p.R50X mutation. The latter accounts for more than 50% of the mutated alleles in most Caucasian patient populations. Mutations resulting in PTC could trigger the degradation of mRNA through a mechanism known as nonsense mediated decay (NMD). To investigate if NMD affects the levels of transcripts containing PYGM mutations, 28 Spanish patients with McArdle disease, harboring 17 different mutations with PTCs in 77% of their alleles, were studied. Transcripts levels of PYGM were measured and sequenced. We assessed that 92% of patients showed NMD. The most frequent mutation (p.R50X) elicited decay in all the genotypes tested. Other PTC producing mutations resulting in NMD were: p.L5VfsX22, p.Q73HfsX7, p.E125X, p.N134KfsX161, p.W388SfsX34, p.R491AfsX7, and p.D534VfsX5. Located in the last exon, the mutation p.E797VfsX19 was not affected by NMD. Missense mutations did not appear to be affected by NMD. In the cDNA sequences they appeared as homozygous, despite being heterozygous in the genomic DNA sequences. Exceptions to the rules governing NMD were found in the mutations p.A704 V and p.K754NfsX49.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Expression of the muscle glycogen phosphorylase gene in patients with McArdle disease: the role of nonsense-mediated mRNA decay

et al. 2008

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“…The present results confirm that the seventeen mutations reported earlier [2,4,[33][34][35][36][37] and the one described here that affect the UFSD of CPS1 in patients with CPS1D…”

Section: Discussionsupporting

confidence: 92%

“…found in CPS1D patients [2,4,[33][34][35][36][37] and to clarify the role and importance of the UFSD. When expression was possible, we studied the properties of the purified mutant enzyme forms, comparing them with wild-type human CPS1.…”

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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“…Glycine at amino acid position 982 is evolutionarily conserved from yeast to human, and is predicted to be deleterious by computer algorithms, SIFT [10] and PolyPhen [11]. Two other variants at the same amino acid position, c.2945G>A (p.G982D) and c.2944G>A (p.G982S), have been previously reported in patients with CPSI deficiency [12,13]. Collectively, these data suggested that the c.2945G>T (p.G982V) variant was likely pathogenic.…”

Section: Clinical Descriptionsmentioning

confidence: 99%

Molecular characterization of CPS1 deletions by array CGH

Wang

Shchelochkov

Zhan

et al. 2011

Molecular Genetics and Metabolism

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CPSI deficiency usually results in severe hyperammonemia presenting in the first days of life warranting prompt diagnosis. Most CPS1 defects are non-recurrent, private mutations, including point mutation, small insertions and deletions. In this study, we report the detection of large deletions varying from 1.4 kb to >130 kb in the CPS1 gene of 4 unrelated patients by targeted array CGH. These results underscore the importance of analysis of large deletions when only one mutation or no mutations are identified in cases where CPSI deficiency is strongly indicated.

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The frequent observation of evidence for nonsense-mediated decay in RNA from patients with carbamyl phosphate synthetase I deficiency

Cited by 16 publications

References 17 publications

Expression of the muscle glycogen phosphorylase gene in patients with McArdle disease: the role of nonsense-mediated mRNA decay

Expression of the muscle glycogen phosphorylase gene in patients with McArdle disease: the role of nonsense-mediated mRNA decay

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 characterization of CPS1 deletions by array CGH

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