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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
ß-Ureidopropionase deficiency: Phenotype, genotype and protein structural consequences in 16 patients
Biochimica et Biophysica Acta - Molecular Basis of Disease, Volume 1822, No. 7, Year 2012
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Description
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. © 2012 Elsevier B.V.
Authors & Co-Authors
Van Kuilenburg, André B.P.
Netherlands, Amsterdam
Emma Kinderziekenhuis
Dobritzsch, Doreen
Sweden, Stockholm
Karolinska Institutet
Meijer, Judith
Netherlands, Amsterdam
Emma Kinderziekenhuis
Krumpel, Michael
Sweden, Stockholm
Karolinska Institutet
Selim, Laila Abdel Moteleb
Egypt, Cairo
Faculty of Medicine
Rashed, Mohamed S.
Egypt, Giza
Pharmagene Laboratory
Assmann, Birgit E.
Germany, Dusseldorf
Universitätsklinikum Düsseldorf
Meinsma, Rutger
Netherlands, Amsterdam
Emma Kinderziekenhuis
Lohkamp, Bernhard
Sweden, Stockholm
Karolinska Institutet
Ito, Tetsuya
Japan, Nagoya
Nagoya City University Graduate School of Medical Sciences
Abeling, Nico G.G.M.
Netherlands, Amsterdam
Emma Kinderziekenhuis
Saito, Kayoko
Japan, Tokyo
Tokyo Women's Medical University
Eto, Kaoru
Japan, Tokyo
Tokyo Women's Medical University
Smitka, Martin
Germany, Dresden
Technische Universität Dresden
Engvall, Martin L.
Sweden, Stockholm
Karolinska Universitetssjukhuset
Zhang, Chunhua
Japan, Kanazawa
Mils International
Xu, Wang
China, Beijing
Beijing Children's Hospital, Capital Medical University
Zoetekouw, Lida
Netherlands, Amsterdam
Emma Kinderziekenhuis
Hennekam, Raoul C.M.
Netherlands, Amsterdam
Emma Kinderziekenhuis
Statistics
Citations: 31
Authors: 19
Affiliations: 11
Identifiers
Doi:
10.1016/j.bbadis.2012.04.001
ISSN:
09254439
e-ISSN:
1879260X
Research Areas
Cancer
Genetics And Genomics