Journal Article

β-Ureidopropionase deficiency: an inborn error of pyrimidine degradation associated with neurological abnormalities

André B.P. van Kuilenburg, Rutger Meinsma, Eva Beke, Birgit Assmann, Antonia Ribes, Isabel Lorente, Rebekka Busch, Ertan Mayatepek, Nico G.G.M. Abeling, Arno van Cruchten, Alida E.M. Stroomer, Henk van Lenthe, Lida Zoetekouw, Willem Kulik, Georg F. Hoffmann, Thomas Voit, Ron A. Wevers, Frank Rutsch and Albert H. van Gennip

in Human Molecular Genetics

Volume 13, issue 22, pages 2793-2801
Published in print November 2004 | ISSN: 0964-6906
Published online September 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddh303
β-Ureidopropionase deficiency: an inborn error of pyrimidine degradation associated with neurological abnormalities

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β-Ureidopropionase deficiency is an inborn error of the pyrimidine degradation pathway, affecting the cleavage of N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyric acid. In this study, we report the elucidation of the genetic basis underlying a β-ureidopropionase deficiency in four patients presenting with neurological abnormalities and strongly elevated levels of N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyric acid in plasma, cerebrospinal fluid and urine. No β-ureidopropionase activity could be detected in a liver biopsy obtained from one of the patients, which reflected the complete absence of the β-ureidopropionase protein. Analysis of the β-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 β-ureidopropionase enzyme without residual activity. Our results demonstrate that the N-carbamyl-β-amino aciduria in these patients is due to a deficiency of β-ureidopropionase, which is caused by mutations in the UPB1 gene. Furthermore, an altered homeostasis of β-aminoisobutyric acid and/or increased oxidative stress might contribute to some of the clinical abnormalities encountered in patients with a β-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 β-ureidopropionase deficiency might not be as rare as is generally considered.

Journal Article.  5464 words.  Illustrated.

Subjects: Genetics and Genomics

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