ß-Ureidopropionase deficiency: Phenotype, genotype and protein structural consequences in 16 patients

André B.P. Van Kuilenburg, Doreen Dobritzsch, Judith Meijer, Michael Krumpel, Laila A. Selim, Mohamed S. Rashed, Birgit Assmann, Rutger Meinsma, Bernhard Lohkamp, Tetsuya Ito, Nico G.G.M. Abeling, Kayoko Saito, Kaoru Eto, Martin Smitka, Martin Engvall, Chunhua Zhang, Wang Xu, Lida Zoetekouw, Raoul C.M. Hennekam

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16 引用 (Scopus)

抜粋

ß-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyzes the conversion of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid to ß-alanine and ß-aminoisobutyric acid, ammonia and CO 2. To date, only five genetically confirmed patients with a complete ß-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 11 newly identified ß-ureidopropionase deficient patients as well as the analysis of the mutations in a three-dimensional framework. Patients presented mainly with neurological abnormalities (intellectual disabilities, seizures, abnormal tonus regulation, microcephaly, and malformations on neuro-imaging) and markedly elevated levels of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid in urine and plasma. Analysis of UPB1, encoding ß-ureidopropionase, showed 6 novel missense mutations and one novel splice-site mutation. Heterologous expression of the 6 mutant enzymes in Escherichia coli showed that all mutations yielded mutant ß-ureidopropionase proteins with significantly decreased activity. Analysis of a homology model of human ß-ureidopropionase generated using the crystal structure of the enzyme from Drosophila melanogaster indicated that the point mutations p.G235R, p.R236W and p.S264R lead to amino acid exchanges in the active site and therefore affect substrate binding and catalysis. The mutations L13S, R326Q and T359M resulted most likely in folding defects and oligomer assembly impairment. Two mutations were identified in several unrelated ß-ureidopropionase patients, indicating that ß-ureidopropionase deficiency may be more common than anticipated.

元の言語English
ページ(範囲)1096-1108
ページ数13
ジャーナルBiochimica et Biophysica Acta - Molecular Basis of Disease
1822
発行部数7
DOI
出版物ステータスPublished - 07-2012

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

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    Van Kuilenburg, A. B. P., Dobritzsch, D., Meijer, J., Krumpel, M., Selim, L. A., Rashed, M. S., Assmann, B., Meinsma, R., Lohkamp, B., Ito, T., Abeling, N. G. G. M., Saito, K., Eto, K., Smitka, M., Engvall, M., Zhang, C., Xu, W., Zoetekouw, L., & Hennekam, R. C. M. (2012). ß-Ureidopropionase deficiency: Phenotype, genotype and protein structural consequences in 16 patients. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1822(7), 1096-1108. https://doi.org/10.1016/j.bbadis.2012.04.001