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beta-Ureidopropiona...
beta-Ureidopropionase deficiency due to novel and rare UPB1 mutations affecting pre-mRNA splicing and protein structural integrity and catalytic activity
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- Dobritzsch, Doreen, 1972- (författare)
- Uppsala universitet,Biokemi
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- Meijer, Judith (författare)
- Univ Amsterdam, Amsterdam Univ, Canc Ctr Amsterdam, Med Ctr,Lab Genet Metab Dis,Amsterdam Gastroentero, Amsterdam, Netherlands.
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- Meinsma, Rutger (författare)
- Univ Amsterdam, Amsterdam Univ, Canc Ctr Amsterdam, Med Ctr,Lab Genet Metab Dis,Amsterdam Gastroentero, Amsterdam, Netherlands.
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- Maurer, Dirk (författare)
- Cytiva, Uppsala, Sweden.
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- Monavari, Ardeshir A. (författare)
- Childrens Hlth Ireland Temple St, Natl Ctr Inherited Metab Disorders, Temple St, Dublin, Ireland.
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- Gummesson, Anders (författare)
- Sahlgrens Univ Hosp, Dept Clin Genet & Genom, Gothenburg, Sweden.
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- Reims, Annika (författare)
- Queen Silv Childrens Hosp, Gothenburg, Sweden.
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- Cayuela, Jorge A. (författare)
- Sahlgrens Univ Hosp, Dept Clin Genet & Genom, Gothenburg, Sweden.
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- Kuklina, Natalia (författare)
- Drammen Hosp, Habilitat Ctr, Pediat Dept, Vestre Viken HF, Drammen, Norway.
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- Benoist, Jean-Francois (författare)
- Hop Univ Robert Debre, Serv Biochim Hormonol, Paris, France.
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- Perrin, Laurence (författare)
- Hop Univ Robert Debre, Serv Biochim Hormonol, Paris, France.
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- Assmann, Birgit (författare)
- Univ Childrens Hosp, Univ Heidelberg, Heidelberg, Germany.
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- Hoffmann, Georg F. (författare)
- Univ Childrens Hosp, Univ Heidelberg, Heidelberg, Germany.
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- Bierau, Jörgen (författare)
- Maastricht Univ Med Ctr, Dept Clin Genet, Maastricht, Netherlands.;Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands.
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- Kaindl, Angela M. (författare)
- Charite Univ Med Berlin, Inst Cell & Neurobiol, Ctr Chronically Sick Children, Dept Pediat Neurol, Berlin, Germany.
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- Kuilenburg, Andre B. P. van (författare)
- Univ Amsterdam, Amsterdam Univ, Canc Ctr Amsterdam, Med Ctr,Lab Genet Metab Dis,Amsterdam Gastroentero, Amsterdam, Netherlands.;Amsterdam UMC, Lab Genet Metab Dis, Locat AMC,F0-220,Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands.
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(creator_code:org_t)
- Elsevier, 2022
- 2022
- Engelska.
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Ingår i: Molecular Genetics and Metabolism. - : Elsevier. - 1096-7192 .- 1096-7206. ; 136:3, s. 177-185
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Nyckelord
- beta-Ureidopropionase
- UPB1
- Neurological abnormalities
- Crystal structure
- Minigene approach
- Functional and structural protein analysis
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas
- Av författaren/redakt...
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Dobritzsch, Dore ...
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Meijer, Judith
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Meinsma, Rutger
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Maurer, Dirk
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Monavari, Ardesh ...
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Gummesson, Ander ...
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visa fler...
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Reims, Annika
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Cayuela, Jorge A ...
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Kuklina, Natalia
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Benoist, Jean-Fr ...
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Perrin, Laurence
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Assmann, Birgit
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Hoffmann, Georg ...
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Bierau, Jörgen
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Kaindl, Angela M ...
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Kuilenburg, Andr ...
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- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinska och f ...
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och Medicinsk geneti ...
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Molecular Geneti ...
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Uppsala universitet