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Recurrence of carbamoyl phosphate synthetase 1 (CPS1) deficiency in Turkish patients: Characterization of a founder mutation by use of recombinant CPS1 from insect cells expression

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dc.contributor.authorHu, Liyan
dc.contributor.authorDiez-Fernandez, Carmen
dc.contributor.authorRuefenacht, Veronique
dc.contributor.authorHismi, Burcu Ozturk
dc.contributor.authorUnal, Ozlem
dc.contributor.authorSOYUÇEN, ERDOĞAN
dc.contributor.authorÇOKER, MAHMUT
dc.contributor.authorBAYRAKTAR, Bilge
dc.contributor.authorGunduz, Mehmet
dc.contributor.authorKIYKIM, Ertuğrul
dc.contributor.authorOlgac, Asburce
dc.contributor.authorPerez-Tur, Jordi
dc.contributor.authorRubio, Vicente
dc.contributor.authorHaeberle, Johannes
dc.contributor.institutionauthorBAYRAKTAR, BILGE
dc.date.accessioned2020-10-22T18:35:06Z
dc.date.available2020-10-22T18:35:06Z
dc.date.issued2014-12-01T00:00:00Z
dc.description.abstractCarbamoyl phosphate synthetase 1 (CPS1) deficiency due to CPS1 mutations is a rare autosomal-recessive urea cycle disorder causing hyperammonemia that can lead to death or severe neurological impairment. CPS1 catalyzes carbamoyl phosphate formation from ammonia, bicarbonate and two molecules of ATP, and requires the allosteric activator N-acetyl-L-glutamate. Clinical mutations occur in the entire CPS1 coding region, but mainly in single families, with little recurrence. We characterized here the only currently known recurrent CPS1 mutation, p.Val1013del, found in eleven unrelated patients of Turkish descent using recombinant His-tagged wild type or mutant CPS1 expressed in baculovirus/insect cell system. The global CPS1 reaction and the ATPase and ATP synthesis partial reactions that reflect, respectively, the bicarbonate and the carbamate phosphorylation steps, were assayed. We found that CPS1 wild type and V1013del mutant showed comparable expression levels and purity but the mutant CPS1 exhibited no significant residual activities. In the CPS1 structural model, V1013 belongs to a highly hydrophobic beta-strand at the middle of the central beta-sheet of the A subdomain of the carbamate phosphorylation domain and is close to the predicted carbamate tunnel that links both phosphorylation sites. Haplotype studies suggested that p.Val1013del is a founder mutation. In conclusion, the mutation p.V1013del inactivates CPS1 but does not render the enzyme grossly unstable or insoluble. Recurrence of this particular mutation in Turkish patients is likely due to a founder effect, which is consistent with the frequent consanguinity observed in the affected population. (C) 2014 Elsevier Inc All rights reserved.
dc.identifier.citationHu L., Diez-Fernandez C., Ruefenacht V., Hismi B. O. , Unal O., SOYUÇEN E., ÇOKER M., BAYRAKTAR B., Gunduz M., KIYKIM E., et al., -Recurrence of carbamoyl phosphate synthetase 1 (CPS1) deficiency in Turkish patients: Characterization of a founder mutation by use of recombinant CPS1 from insect cells expression-, MOLECULAR GENETICS AND METABOLISM, cilt.113, ss.267-273, 2014
dc.identifier.doi10.1016/j.ymgme.2014.09.014
dc.identifier.pubmed25410056
dc.identifier.scopus84919342845
dc.identifier.urihttp://hdl.handle.net/20.500.12645/24212
dc.identifier.wosWOS:000346623000006
dc.titleRecurrence of carbamoyl phosphate synthetase 1 (CPS1) deficiency in Turkish patients: Characterization of a founder mutation by use of recombinant CPS1 from insect cells expression
dc.typeArticle
dspace.entity.typePublication
local.avesis.id93d32cea-5585-42e1-98f3-86ad20023875
local.publication.isinternational1
relation.isAuthorOfPublication0c519bac-cbcb-4931-89f6-451ca267749b
relation.isAuthorOfPublication.latestForDiscovery0c519bac-cbcb-4931-89f6-451ca267749b
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