β-Ureidopropionase deficiency due to novel and rare UPB1 mutations affecting pre-mRNA splicing and protein structural integrity and catalytic activity
| Autor: | 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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| Přispěvatelé: | Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Clinical Genetics, MUMC+: DA KG Lab Centraal Lab (9), RS: FHML non-thematic output |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Purine-Pyrimidine Metabolism
Inborn Errors Endocrinology Diabetes and Metabolism beta-Ureidopropionase Minigene approach Biochemistry AMINOISOBUTYRIC ACID Amidohydrolases MECHANISMS Neurological abnormalities Endocrinology SDG 3 - Good Health and Well-being GENETIC-ANALYSIS Genetics RNA Precursors Animals Humans Abnormalities Multiple CRYSTAL-STRUCTURE WHITE FAT HOMOCARNOSINE Molecular Biology Medicinsk genetik Functional and structural protein analysis Mammals Brain Diseases Movement Disorders PURIFICATION Crystal structure UPB1 DIHYDROPYRIMIDINE DEHYDROGENASE ALANINE SYNTHASE Mutation beta-Alanine CARNOSINE Medical Genetics ß-Ureidopropionase |
| Zdroj: | Molecular genetics and metabolism, 136(3), 177-185. Academic Press Inc. Molecular Genetics and Metabolism, 136(3), 177-185. Academic Press Molecular Genetics and Metabolism, 136(3), 177-185. Academic Press Inc. |
| ISSN: | 1096-7192 |
| DOI: | 10.1016/j.ymgme.2022.01.102 |
| Popis: | beta-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyses the conversion of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid to beta-alanine and beta-aminoisobutyric acid, ammonia and CO2. To date, only a limited number of genetically confirmed patients with a complete beta-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 10 newly identified beta-ureidopropionase deficient individuals. Patients presented mainly with neurological abnormalities and markedly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in urine. Analysis of UPB1, encoding beta-ureidopropionase, showed 5 novel missense variants and two novel splice-site variants. Functional expression of the UPB1 variants in mammalian cells showed that recombinant beta-ureidopropionase carrying the p.Ala120Ser, p.Thr129Met, p.Ser300Leu and p.Asn345Ile variant yielded no or significantly decreased beta-ureidopropionase activity. Analysis of the crystal structure of human beta-ureidopropionase indicated that the point mutations affect substrate binding or prevent the proper subunit association to larger oligomers and thus a fully functional beta-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 beta-ureidopropionase patients, indicating that beta-ureidopropionase deficiency may be more common than anticipated. |
| Databáze: | OpenAIRE |
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