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

• Verfasst von: Dobritzsch, Doreen [VerfasserIn]
• Verfasst von: Meijer, Judith [VerfasserIn]
• Verfasst von: Meinsma, Rutger [VerfasserIn]
• Verfasst von: Maurer, Dirk [VerfasserIn]
• Verfasst von: Monavari, Ardeshir A. [VerfasserIn]
• Verfasst von: Gummesson, Anders [VerfasserIn]
• Verfasst von: Reims, Annika [VerfasserIn]
• Verfasst von: Cayuela, Jorge A. [VerfasserIn]
• Verfasst von: Kuklina, Natalia [VerfasserIn]
• Verfasst von: Benoist, Jean-François [VerfasserIn]
• Verfasst von: Perrin, Laurence [VerfasserIn]
• Verfasst von: Assmann, Birgit [VerfasserIn]
• Verfasst von: Hoffmann, Georg F. [VerfasserIn]
• Verfasst von: Bierau, Jörgen [VerfasserIn]
• Verfasst von: Kaindl, Angela M. [VerfasserIn]
• Verfasst von: van Kuilenburg, André B. P. [VerfasserIn]
• Titel: β-Ureidopropionase deficiency due to novel and rare UPB1 mutations affecting pre-mRNA splicing and protein structural integrity and catalytic activity
• Verf.angabe: 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
• E-Jahr: 2022
• Jahr: 13 June 2022
• Umfang: 9 S.
• Fussnoten: Gesehen am 08.08.2022
• Titel Quelle: Enthalten in: Molecular genetics and metabolism
• Ort Quelle: Orlando, Fla. : Academic Press, 1998
• Jahr Quelle: 2022
• Band/Heft Quelle: 136(2022), 3, Seite 177-185
• ISSN Quelle: 1096-7206
• DOI: doi:10.1016/j.ymgme.2022.01.102
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Crystal structure
• Sach-SW: Functional and structural protein analysis
• Sach-SW: Minigene approach
• Sach-SW: Neurological abnormalities
• Sach-SW: ß-Ureidopropionase
• K10plus-PPN: 181340819X

Abstract

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.