Variant in the allosteric domain of CPS1 protein associated with effectiveness of N-carbamoyl glutamate therapy in neonatal onset CPS1 deficiency
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Vincenza Gragnaniello
Abstract
Objectives
Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a severe urea cycle disorder. Patients can present with hyperammonemic coma in the first days of life. Treatment includes nitrogen scavengers, reduced protein intake and supplementation with L-arginine and/or L-citrulline. N-carbamoyl glutamate (NCG) has been hypothesized to stimulate the residual CPS1 function, although only few patients are reported.
Case presentation
We report a patient with neonatal-onset CPS1 deficiency who received NCG in association with nitrogen scavenger and L-citrulline. The patient carried the novel variants CPS1-c.2447A>G p.(Gln816Arg) and CPS1-c.4489T>C p.(Tyr1497His). The latter is localized in the C-terminal allosteric domain of the protein, and is implicated in the binding of the natural activator N-acetyl-L-glutamate. NCG therapy was effective in controlling ammonia levels, allowing to increase the protein intake.
Conclusions
Our data show that the response to NCG can be indicated based on the protein structure. We hypothesize that variants in the C-terminal domain may be responsive to NCG therapy.
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Research funding: None declared.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: Authors state no conflict of interest.
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Informed consent: Informed consent was obtained from all individuals included in this study.
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Ethical approval: The local Institutional Review Board deemed the study exempt from review.
References
1. Häberle, J, Burlina, A, Chakrapani, A, Dixon, M, Karall, D, Lindner, M, et al.. Suggested guidelines for the diagnosis and management of urea cycle disorders: first revision. J Inherit Metab Dis 2019;42:1192–230. https://doi.org/10.1002/jimd.12100.Search in Google Scholar PubMed
2. Rokicki, D, Pajdowska, M, Trubicka, J, Thong, MK, Ciara, E, Piekutowska-Abramczuk, D, et al.. 3-Methylglutaconic aciduria, a frequent but underrecognized finding in carbamoyl phosphate synthetase I deficiency. Clin Chim Acta 2017;471:95–100. https://doi.org/10.1016/j.cca.2017.05.023.Search in Google Scholar PubMed
3. Ah Mew, N, McCarter, R, Daikhin, Y, Lichter-Konecki, U, Nissim, I, Yudkoff, M, et al.. Augmenting ureagenesis in patients with partial carbamyl phosphate synthetase 1 deficiency with N-carbamyl-l-glutamate. J Pediatr 2014;165:401–3.e3. https://doi.org/10.1016/j.jpeds.2014.04.012.Search in Google Scholar PubMed PubMed Central
4. de Cima, S, Polo, LM, Díez-Fernández, C, Martínez, AI, Cervera, J, Fita, I, et al.. Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis. Sci Rep 2015;5:16950. https://doi.org/10.1038/srep16950.Search in Google Scholar PubMed PubMed Central
5. Yap, S, Gougeard, N, Hart, AR, Barcelona, B, Rubio, V. N‐wcarbamoylglutamate‐responsive carbamoyl phosphate synthetase 1 (CPS1) deficiency: a patient with a novel CPS1 mutation and an experimental study on the mutation’s effects. JIMD Rep 2019;48:36–44. https://doi.org/10.1002/jmd2.12034.Search in Google Scholar PubMed PubMed Central
6. Diez-Fernandez, C, Häberle, J. Targeting CPS1 in the treatment of Carbamoyl phosphate synthetase 1 (CPS1) deficiency, a urea cycle disorder. Expert Opin Ther Targets 2017;21:391–9. https://doi.org/10.1080/14728222.2017.1294685.Search in Google Scholar PubMed
7. Shi, D, Zhao, G, Ah Mew, N, Tuchman, M. Precision medicine in rare disease: mechanisms of disparate effects of N-carbamyl-l-glutamate on mutant CPS1 enzymes. Mol Genet Metabol 2017;120:198–206. https://doi.org/10.1016/j.ymgme.2016.12.002.Search in Google Scholar PubMed PubMed Central
8. Marshall, M, Fahien, LA. Proteolysis as a probe of ligand-associated conformational changes in rat carbamyl phosphate synthetase I. Arch Biochem Biophys 1988;262:455–70. https://doi.org/10.1016/0003-9861(88)90397-9.Search in Google Scholar PubMed
9. Pekkala, S, . Understanding carbamoyl-phosphate synthetase 1 (CPS1) deficiency by using expression studies and structure-based analysis. Hum Mutat 2010;31:801–8. https://doi.org/10.1002/humu.21272.Search in Google Scholar PubMed
10. Sugiyama, Y, Shimura, M, Ogawa-Tominaga, M, Ebihara, T, Kinouchi, Y, Isozaki, K, et al.. Therapeutic effect of N-carbamylglutamate in CPS1 deficiency. Mol Genet Metab Rep 2020;24:100622. https://doi.org/10.1016/j.ymgmr.2020.100622.Search in Google Scholar PubMed PubMed Central
11. Choi, Y, Oh, A, Lee, Y, Kim, GH, Choi, JH, Yoo, HW, et al.. Unfavorable clinical outcomes in patients with carbamoyl phosphate synthetase 1 deficiency. Clin Chim Acta 2022;526:55–61. https://doi.org/10.1016/j.cca.2021.11.029.Search in Google Scholar PubMed
12. Lin, HT, Enchautegui-Colon, Y, Huang, YR, Zimmerman, C, DeMarzo, D, Tsai, ACH. Novel compound heterozygote variants: c.4193_4206delinsG (p.Leu1398Argfs*25), c.793C > A (p.Pro265Thr), in the CPS1 gene (NM_001875.4) causing late onset carbamoyl phosphate synthetase 1 deficiency—lessons learned. Mol Gen Metab Rep 2022;33:100942. https://doi.org/10.1016/j.ymgmr.2022.100942.Search in Google Scholar PubMed PubMed Central
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- Variant in the allosteric domain of CPS1 protein associated with effectiveness of N-carbamoyl glutamate therapy in neonatal onset CPS1 deficiency
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- Successful treatment of hypercalcemia in a Chinese patient with a novel homozygous mutation in the CYP24A1 gene using zoledronic acid: a case report
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Articles in the same Issue
- Frontmatter
- Review
- Systematic literature review of the epidemiology of glycogen storage disease type 1a
- Original Articles
- Excessive weight gain among preschool children during the COVID-19 lockdown in China: a retrospective observational study
- Longitudinal assessment of bone health index as a measure of bone health in short-statured children before and during treatment with recombinant growth hormone
- First results of the growth disorders related twinning programme Partners4Growth implemented at the tertiary university pediatric endocrinology clinics in Bulgaria
- Predictive factors of catch-up growth in term, small for gestational age infants: a two-year prospective observational study in Algeria
- Glucose levels are not the same for everyone: a real-world big data study evaluating fasting serum glucose levels by sex and age among children
- The status and childcare management of overweight and obesity among preschool children in Hangzhou
- The relationship between metabolic syndrome criteria and pentraxin-3 levels in children
- Case Reports
- Variant in the allosteric domain of CPS1 protein associated with effectiveness of N-carbamoyl glutamate therapy in neonatal onset CPS1 deficiency
- Rickets in proximal renal tubular acidosis: a case series of six distinct etiologies
- Successful treatment of hypercalcemia in a Chinese patient with a novel homozygous mutation in the CYP24A1 gene using zoledronic acid: a case report
- A novel mutation in the AMHR2 gene, resulting in persistent Müllerian duct syndrome presenting with bilateral cryptorchidism and obstructed inguinal hernia
- Syndrome of inappropriate secretion of anti-diuretic hormone due to hypothalamic hamartoma: use of tolvaptan
- Letter to the Editor
- CD163+ and CD14+ macrophages are increased in obese children
