title: ß-ureidopropionase deficiency: phenotype, genotype and protein structural consequences in 16 patients.
abstract: 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.
authors.affiliation: Academic Medical Center, Emma Children's Hospital, Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, 1105 AZ Amsterdam, The Netherlands. a.b.vanKuilenburg@amc.uva.nl
authors.forename: André B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.forename: Doreen
authors.initials: D
authors.lastname: Dobritzsch
authors.forename: Judith
authors.initials: J
authors.lastname: Meijer
authors.forename: Michael
authors.initials: M
authors.lastname: Krumpel
authors.forename: Laila A
authors.initials: LA
authors.lastname: Selim
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Rashed
authors.forename: Birgit
authors.initials: B
authors.lastname: Assmann
authors.forename: Rutger
authors.initials: R
authors.lastname: Meinsma
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lohkamp
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ito
authors.forename: Nico G G M
authors.initials: NG
authors.lastname: Abeling
authors.forename: Kayoko
authors.initials: K
authors.lastname: Saito
authors.forename: Kaoru
authors.initials: K
authors.lastname: Eto
authors.forename: Martin
authors.initials: M
authors.lastname: Smitka
authors.forename: Martin
authors.initials: M
authors.lastname: Engvall
authors.forename: Chunhua
authors.initials: C
authors.lastname: Zhang
authors.forename: Wang
authors.initials: W
authors.lastname: Xu
authors.forename: Lida
authors.initials: L
authors.lastname: Zoetekouw
authors.forename: Raoul C M
authors.initials: RC
authors.lastname: Hennekam
mesh_terms: D000328:Adult; D000581:Amidohydrolases / Q000172:deficiency* / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000502:physiology; D000621:Aminoisobutyric Acids / Q000097:blood / Q000652:urine; D000818:Animals; D055162:Biocatalysis; D020134:Catalytic Domain / Q000502:physiology; D002493:Central Nervous System Diseases / Q000201:enzymology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004331:Drosophila melanogaster; D004926:Escherichia coli; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D017354:Point Mutation; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics*; D011743:Pyrimidines / Q000378:metabolism*; D044469:Racial Groups / Q000235:genetics; D015091:beta-Alanine / Q000097:blood / Q000652:urine
chemical_list: D000621:Aminoisobutyric Acids; D011743:Pyrimidines; D015091:beta-Alanine; D000581:Amidohydrolases; C021590:beta-ureidopropionase; C033435:3-aminoisobutyric acid