Carbamoyl Phosphate Synthetase 1 deficiency in Italy: Clinical and genetic findings in a heterogeneous cohort

Funghini, Silvia; Thusberg, Janita; Spada, Marco; Gasperini, Serena; Parini, Rossella; Ventura, Luisa; Meli, Concetta; Cosmo, Lucrezia De; Sibilio, Michelina; Mooney, Sean D.; Guerrini, Renzo; Morrone, Amelia

doi:10.1016/j.gene.2011.11.052

Cited by 28 publications

(38 citation statements)

References 30 publications

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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%

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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 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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“…Two independent types of CPS1D, neonatal- and late-onset CPS1D, have been differentiated based on age of onset, clinical manifestations and degree of enzymatic activity deficiency. [4] Severe hyperammonemia and severe clinical manifestations are common in neonatal-onset CPS1D. [1] Neonatal-onset patients are often born normally.…”

Section: Discussionmentioning

confidence: 99%

“…CPS1D may have an intermittent course, whereas viral infection or a high-protein diet would induce deterioration. [4,5] …”

Section: Discussionmentioning

confidence: 99%

Neonatal-onset carbamoyl phosphate synthetase I deficiency

et al. 2017

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Rationale:The carbamoyl phosphate synthetase I deficiency (CPS1D) was rare and hard to diagnose due to its atypical symptoms. Brain magnetic resonance imaging (MRI) was typically unavailable in other reports because most patients died before diagnosis was confirmed. Furthermore, it was found a new mutation that had not been described previously.Patient concerns:This is a case of neonatal-onset CPS1D with nonspecific clinical manifestations and deteriorating rapidly. Poor feeding, low activity, and tachypnoea were observed, with rapid progression on day 2 after birth. Severe systematic infection was considered first. However, blood culture and cerebrospinal fluid examination were negative. Symptoms were relief temporarily. Then seizure and tachypnoea reappeared as intravenous amino acids were provided. Further examination indicated severe hyperammonemia (serum ammonia level >500mmol/L). Brain MRI showed diffused white matter lesions.Diagnoses:Genetic analysis revealed 2 heterozygous mutations in the CPS1 gene: c.2407C>G (p.803, R>G) in exon 20 and C.323G>A (p.108, G>E) in exon 4. The diagnosis of CSP1D was confirmed.Interventions:Fasting, the withdrawal of amino acids and plans to treat hyperammonemia were immediately implemented.Outcomes:The parents decided to discontinue medical care.Lessons:Many CPS1D patients died before the diagnoses are confirmed due to its sudden onset, rapid deterioration, atypical symptoms, and low morbidity. Once hyperammonemia is confirmed, blood and urea amino acid analysis in combination with genetic examinations should be performed as early as possible, this approach would help establish diagnoses at an early stage and thus contribute to reducing mortality and improving prognosis.

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“…CPS1D is a rare metabolic condition with a nonspecific biochemical profile thus requiring additional tests . Nowadays, confirmation of the disease is usually done by molecular genetic investigation that led to the reporting of more than 230 CPS1 mutations underlining the genetic heterogeneity at this locus . In recent years, NGS became the preferred method for CPS1 molecular genetic investigation either as part of (often custom‐made) gene panels or of whole exome or genome sequencing.…”

Section: Discussionmentioning

confidence: 99%

Improvement of diagnostic yield in carbamoylphosphate synthetase 1 (CPS1) molecular genetic investigation by RNA sequencing

et al. 2020

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Carbamoylphosphate synthetase 1 (CPS1) deficiency is a rare inborn error of metabolism leading often to neonatal onset hyperammonemia with coma and high mortality. The biochemical features of the disease are nonspecific and cannot distinguish this condition from other defects of the urea cycle, namely N‐acetylglutamate synthase deficiency. Therefore, molecular genetic investigation is required for confirmation of the disease, and nowadays this is done with increasing frequency applying next‐generation sequencing (NGS) techniques. Our laboratory has a long‐standing interest in CPS1 molecular genetic investigation and receives samples from centers in Europe and many other countries. We perform RNA‐based CPS1 molecular genetic investigation as first line investigation and wanted in this study to evaluate our experience with this approach as compared to NGS. In the past 15 years, 297 samples were analyzed, which were referred from 37 countries. CPS1 deficiency could be confirmed in 155 patients carrying 136 different genotypes with only a single mutation recurring more than two times. About 10% of the total 172 variants comprised complex changes (eg, intronic changes possibly affecting splicing, deletions, insertions, or deletions_insertions), which would have been partly missed if only NGS was done. Likewise, RNA analysis was crucial for correct interpretation of at least half of the complex mutations. This study gives highest sensitivity to RNA‐based CPS1 molecular genetic investigation and underlines that NGS should be done together with copy number variation analysis. We propose that unclear cases should be investigated by RNA sequencing in addition, if this method is not used as the initial diagnostic procedure.

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Carbamoyl Phosphate Synthetase 1 deficiency in Italy: Clinical and genetic findings in a heterogeneous cohort

Cited by 28 publications

References 30 publications

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

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

Neonatal-onset carbamoyl phosphate synthetase I deficiency

Improvement of diagnostic yield in carbamoylphosphate synthetase 1 (CPS1) molecular genetic investigation by RNA sequencing

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