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β-Ureidopropionase deficiency due to novel and rare UPB1 mutations affecting pre-mRNA splicing and protein structural integrity and catalytic activity

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β-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyses the conversion of N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyric acid to β-alanine and β-aminoisobutyric acid, ammonia and CO2. To date, only a limited number of genetically confirmed patients with a co...

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Main Authors: Dobritzsch, Doreen (Author) , Meijer, Judith (Author) , Meinsma, Rutger (Author) , Maurer, Dirk (Author) , Monavari, Ardeshir A. (Author) , Gummesson, Anders (Author) , Reims, Annika (Author) , Cayuela, Jorge A. (Author) , Kuklina, Natalia (Author) , Benoist, Jean-François (Author) , Perrin, Laurence (Author) , Assmann, Birgit (Author) , Hoffmann, Georg F. (Author) , Bierau, Jörgen (Author) , Kaindl, Angela M. (Author) , van Kuilenburg, André B. P. (Author)
Format: Article (Journal)
Language:English
Published: 13 June 2022
In: Molecular genetics and metabolism
Year: 2022, Volume: 136, Issue: 3, Pages: 177-185
ISSN:1096-7206
DOI:10.1016/j.ymgme.2022.01.102
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ymgme.2022.01.102
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1096719222001305
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Author Notes:Doreen Dobritzsch, Judith Meijer, Rutger Meinsma, Dirk Maurer, Ardeshir A. Monavari, Anders Gummesson, Annika Reims, Jorge A. Cayuela, Natalia Kuklina, Jean-François Benoist, Laurence Perrin, Birgit Assmann, Georg F. Hoffmann, Jörgen Bierau, Angela M. Kaindl, André B.P. van Kuilenburg
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Summary:β-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyses the conversion of N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyric acid to β-alanine and β-aminoisobutyric acid, ammonia and CO2. To date, only a limited number of genetically confirmed patients with a complete β-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 10 newly identified β-ureidopropionase deficient individuals. Patients presented mainly with neurological abnormalities and markedly elevated levels of N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyric acid in urine. Analysis of UPB1, encoding β-ureidopropionase, showed 5 novel missense variants and two novel splice-site variants. Functional expression of the UPB1 variants in mammalian cells showed that recombinant ß-ureidopropionase carrying the p.Ala120Ser, p.Thr129Met, p.Ser300Leu and p.Asn345Ile variant yielded no or significantly decreased β-ureidopropionase activity. Analysis of the crystal structure of human ß-ureidopropionase indicated that the point mutations affect substrate binding or prevent the proper subunit association to larger oligomers and thus a fully functional β-ureidopropionase. A minigene approach showed that the intronic variants c.[364 + 6 T > G] and c.[916 + 1_916 + 2dup] led to skipping of exon 3 and 8, respectively, in the process of UPB1 pre-mRNA splicing. The c.[899C > T] (p.Ser300Leu) variant was identified in two unrelated Swedish β-ureidopropionase patients, indicating that β-ureidopropionase deficiency may be more common than anticipated.
Item Description:Gesehen am 08.08.2022
Physical Description:Online Resource
ISSN:1096-7206
DOI:10.1016/j.ymgme.2022.01.102

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