beta-Ureidopropionase deficiency: an inborn error of pyrimidine degradation associated with neurological abnormalities.
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.
van Kuilenburg
André B P
AB
Department of Clinical Chemistry, Emma Children's Hospital, The Netherlands. a.b.vankuilenburg@amc.uva.nl
Meinsma
Rutger
R
Beke
Eva
E
Assmann
Birgit
B
Ribes
Antonia
A
Lorente
Isabel
I
Busch
Rebekka
R
Mayatepek
Ertan
E
Abeling
Nico G G M
NG
van Cruchten
Arno
A
Stroomer
Alida E M
AE
van Lenthe
Henk
H
Zoetekouw
Lida
L
Kulik
Willem
W
Hoffmann
Georg F
GF
Voit
Thomas
T
Wevers
Ron A
RA
Rutsch
Frank
F
van Gennip
Albert H
AH
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
D000621:Aminoisobutyric Acids; D011743:Pyrimidines; D015091:beta-Alanine; D000581:Amidohydrolases; C021590:beta-ureidopropionase; C030986:pyrimidine; C033435:3-aminoisobutyric acid