title: beta-Ureidopropionase deficiency: an inborn error of pyrimidine degradation associated with neurological abnormalities.
abstract: beta-Ureidopropionase deficiency is an inborn error of the pyrimidine degradation pathway, affecting the cleavage of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid. In this study, we report the elucidation of the genetic basis underlying a beta-ureidopropionase deficiency in four patients presenting with neurological abnormalities and strongly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in plasma, cerebrospinal fluid and urine. No beta-ureidopropionase activity could be detected in a liver biopsy obtained from one of the patients, which reflected the complete absence of the beta-ureidopropionase protein. Analysis of the beta-ureidopropionase gene (UPB1) of these patients revealed the presence of two splice-site mutations (IVS1-2A>G and IVS8-1G>A) and one missense mutation (A85E). Heterologous expression of the mutant enzyme in Escherichia coli showed that the A85E mutation resulted in a mutant beta-ureidopropionase enzyme without residual activity. Our results demonstrate that the N-carbamyl-beta-amino aciduria in these patients is due to a deficiency of beta-ureidopropionase, which is caused by mutations in the UPB1 gene. Furthermore, an altered homeostasis of beta-aminoisobutyric acid and/or increased oxidative stress might contribute to some of the clinical abnormalities encountered in patients with a beta-ureidopropionase deficiency. An analysis of the presence of the two splice site mutations and the missense mutation in 95 controls identified one individual who proved to be heterozygous for the IVS8-1G>A mutation. Thus, a beta-ureidopropionase deficiency might not be as rare as is generally considered.
authors.affiliation: Department of Clinical Chemistry, Emma Children's Hospital, The Netherlands. a.b.vankuilenburg@amc.uva.nl
authors.forename: André B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.forename: Rutger
authors.initials: R
authors.lastname: Meinsma
authors.forename: Eva
authors.initials: E
authors.lastname: Beke
authors.forename: Birgit
authors.initials: B
authors.lastname: Assmann
authors.forename: Antonia
authors.initials: A
authors.lastname: Ribes
authors.forename: Isabel
authors.initials: I
authors.lastname: Lorente
authors.forename: Rebekka
authors.initials: R
authors.lastname: Busch
authors.forename: Ertan
authors.initials: E
authors.lastname: Mayatepek
authors.forename: Nico G G M
authors.initials: NG
authors.lastname: Abeling
authors.forename: Arno
authors.initials: A
authors.lastname: van Cruchten
authors.forename: Alida E M
authors.initials: AE
authors.lastname: Stroomer
authors.forename: Henk
authors.initials: H
authors.lastname: van Lenthe
authors.forename: Lida
authors.initials: L
authors.lastname: Zoetekouw
authors.forename: Willem
authors.initials: W
authors.lastname: Kulik
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.forename: Frank
authors.initials: F
authors.lastname: Rutsch
authors.forename: Albert H
authors.initials: AH
authors.lastname: van Gennip
mesh_terms: D000581:Amidohydrolases / Q000172:deficiency* / Q000235:genetics; D000621:Aminoisobutyric Acids / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D002493:Central Nervous System Diseases / Q000201:enzymology / Q000209:etiology / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008099:Liver / Q000201:enzymology; D008297:Male; D009154:Mutation; D018384:Oxidative Stress; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D011743:Pyrimidines / Q000378:metabolism*; D015091:beta-Alanine / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine
chemical_list: D000621:Aminoisobutyric Acids; D011743:Pyrimidines; D015091:beta-Alanine; D000581:Amidohydrolases; C021590:beta-ureidopropionase; C030986:pyrimidine; C033435:3-aminoisobutyric acid