β-Ureidopropionase deficiency: Phenotype, genotype and protein structural consequences in 16 patients

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1822

Article

van Kuilenburg, Andre B. P.¹  Dobritzsch, Doreen²  Meijer, Judith¹  Krumpel, Michael²  Selim, Laila A.^3,4  Rashed, Mohamed S.⁵  Assmann, Birgit⁶  Meinsma, Rutger¹  Lohkamp, Bernhard²  Ito, Tetsuya⁷  Abeling, Nico G. G. M.¹  Saito, Kayoko⁸  Eto, Kaoru⁹  Smitka, Martin¹⁰  Engvall, Martin¹¹  Zhang, Chunhua¹²  Xu, Wang¹³  Zoetekouw, Lida¹  Hennekam, Raoul C. M.¹⁴ 

[1] Univ Amsterdam, Acad Med Ctr, Lab Genet Metab Dis, Emma Childrens Hosp,Dept Clin Chem, NL-1105 AZ Amsterdam, Netherlands

[2] Karolinska Inst, Dept Med Biochem & Biophys MBB, S-17177 Stockholm, Sweden

[3] Cairo Univ, Children Hosp, Dept Pediat, Div Pediat Neurol, Cairo, Egypt

[4] Cairo Univ, Children Hosp, Dept Pediat, Neurometabol Div, Cairo, Egypt

[5] Pharmagene Labs, Giza 12311, Egypt

[6] Univ Childrens Hosp, Dept Gen Pediat, D-40225 Dusseldorf, Germany

[7] Nagoya City Univ, Grad Sch Med Sci, Dept Pediat & Neonatol, Nagoya, Aichi 4678601, Japan

[8] Tokyo Womens Med Univ, Inst Med Genet, Tokyo 1620054, Japan

[9] Tokyo Womens Med Univ, Dept Pediat, Tokyo 1628111, Japan

[10] Univ Dresden, Childrens Hosp, Dept Neuropediat, D-01307 Dresden, Germany

[11] Karolinska Univ Hosp Huddinge, Ctr Inherited Metab Dis, S-14186 Huddinge, Sweden

[12] MILS Int, Dept Res & Dev, Kanazawa, Ishikawa 9218154, Japan

[13] Beijing Childrens Hosp, Beijing, Peoples R China

[14] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, Dept Pediat, NL-1105 AZ Amsterdam, Netherlands

关键词: beta-Ureidopropionase;    UPB1;    Neurological abnormalities;    Homology modeling;    Functional and structural protein analysis;   

DOI  :  10.1016/j.bbadis.2012.04.001

来源: Elsevier

【 摘 要 】

beta-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyzes 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 five genetically confirmed patients with a complete beta-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 11 newly identified beta-ureidopropionase deficient patients as well as the analysis of the mutations in a three-dimensional framework. Patients presented mainly with neurological abnormalities (intellectual disabilities, seizures, abnormal tonus regulation, microcephaly, and malformations on neuro-imaging) and markedly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in urine and plasma. Analysis of UPB1, encoding beta-ureidopropionase, showed 6 novel missense mutations and one novel splice-site mutation. Heterologous expression of the 6 mutant enzymes in Escherichia coli showed that all mutations yielded mutant beta-ureidopropionase proteins with significantly decreased activity. Analysis of a homology model of human beta-ureidopropionase generated using the crystal structure of the enzyme from Drosophila melanogaster indicated that the point mutations p.G235R, p.R236W and p.S264R lead to amino acid exchanges in the active site and therefore affect substrate binding and catalysis. The mutations L13S, R326Q and T359M resulted most likely in folding defects and oligomer assembly impairment. Two mutations were identified in several unrelated beta-ureidopropionase patients, indicating that beta-ureidopropionase deficiency may be more common than anticipated. (c) 2012 Elsevier B.V. All rights reserved.

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