Human Molecular Genetics Advance Access originally published online on September 22, 2004
Human Molecular Genetics 2004 13(22):2793-2801; doi:10.1093/hmg/ddh303
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Human Molecular Genetics, Vol. 13, No. 22 © Oxford University Press 2004; all rights reserved
ß-Ureidopropionase deficiency: an inborn error of pyrimidine degradation associated with neurological abnormalities
1Department of Clinical Chemistry, Academic Medical Center, Emma Children's Hospital, The Netherlands, 2Department of General Pediatrics, University Children's Hospital, Düsseldorf, Germany, 3Institut de Bioquímica Clínica, CDB, Hospital Clínic, Barcelona, Spain, 4Hospital Parc Taulí, Sabadell, Barcelona, Spain, 5Klinik für Kinder- und Jugendmedizin, Klinikum Dortmund gGmbH, Dortmund, Germany, 6Department of Pediatrics, University Hospital Heidelberg, Heidelberg, Germany, 7Department of Pediatrics, University Hospital Essen, Essen, Germany, 8Institute of Neurology, University Medical Center Nijmegen, Nijmegen, The Netherlands and 9Departments of Clinical Genetics and Clinical Chemistry, Academic Hospital Maastricht, Maastricht, The Netherlands
Received July 9, 2004; Accepted September 14, 2004
ß-Ureidopropionase deficiency is an inborn error of the pyrimidine degradation pathway, affecting the cleavage of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid. In this study, we report the elucidation of the genetic basis underlying a ß-ureidopropionase deficiency in four patients presenting with neurological abnormalities and strongly elevated levels of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid in plasma, cerebrospinal fluid and urine. No ß-ureidopropionase activity could be detected in a liver biopsy obtained from one of the patients, which reflected the complete absence of the ß-ureidopropionase protein. Analysis of the ß-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 ß-ureidopropionase enzyme without residual activity. Our results demonstrate that the N-carbamyl-ß-amino aciduria in these patients is due to a deficiency of ß-ureidopropionase, which is caused by mutations in the UPB1 gene. Furthermore, an altered homeostasis of ß-aminoisobutyric acid and/or increased oxidative stress might contribute to some of the clinical abnormalities encountered in patients with a ß-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 ß-ureidopropionase deficiency might not be as rare as is generally considered.
* To whom correspondence should be addressed at: Academic Medical Center, Laboratory Genetic Metabolic Diseases F0-224, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel: +31 205665958; Fax: +31 206962596; Email: a.b.vankuilenburg{at}amc.uva.nl
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