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

André B.P. Van Kuilenburg, Doreen Dobritzsch, Judith Meijer, Michael Krumpel, Laila A. Selim, Mohamed S. Rashed, Birgit Assmann, Rutger Meinsma, Bernhard Lohkamp, Tetsuya Ito, Nico G.G.M. Abeling, Kayoko Saito, Kaoru Eto, Martin Smitka, Martin Engvall, Chunhua Zhang, Wang Xu, Lida Zoetekouw, Raoul C.M. Hennekam

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

ß-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyzes the conversion of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid to ß-alanine and ß-aminoisobutyric acid, ammonia and CO 2. To date, only five genetically confirmed patients with a complete ß-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 11 newly identified ß-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-ß-alanine and N-carbamyl-ß-aminoisobutyric acid in urine and plasma. Analysis of UPB1, encoding ß-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 ß-ureidopropionase proteins with significantly decreased activity. Analysis of a homology model of human ß-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 ß-ureidopropionase patients, indicating that ß-ureidopropionase deficiency may be more common than anticipated.

Original languageEnglish
Pages (from-to)1096-1108
Number of pages13
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1822
Issue number7
DOIs
Publication statusPublished - 01-07-2012

Fingerprint

Aminoisobutyric Acids
Genotype
Phenotype
Mutation
Alanine
Proteins
Enzymes
Microcephaly
Missense Mutation
Mutant Proteins
Carbon Monoxide
Drosophila melanogaster
Catalysis
Ammonia
Point Mutation
Intellectual Disability
Catalytic Domain
Seizures
Urine
Escherichia coli

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

Cite this

Van Kuilenburg, A. B. P., Dobritzsch, D., Meijer, J., Krumpel, M., Selim, L. A., Rashed, M. S., ... Hennekam, R. C. M. (2012). ß-Ureidopropionase deficiency: Phenotype, genotype and protein structural consequences in 16 patients. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1822(7), 1096-1108. https://doi.org/10.1016/j.bbadis.2012.04.001
Van Kuilenburg, André B.P. ; Dobritzsch, Doreen ; Meijer, Judith ; Krumpel, Michael ; Selim, Laila A. ; Rashed, Mohamed S. ; Assmann, Birgit ; Meinsma, Rutger ; Lohkamp, Bernhard ; Ito, Tetsuya ; Abeling, Nico G.G.M. ; Saito, Kayoko ; Eto, Kaoru ; Smitka, Martin ; Engvall, Martin ; Zhang, Chunhua ; Xu, Wang ; Zoetekouw, Lida ; Hennekam, Raoul C.M. / ß-Ureidopropionase deficiency : Phenotype, genotype and protein structural consequences in 16 patients. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2012 ; Vol. 1822, No. 7. pp. 1096-1108.
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abstract = "{\ss}-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyzes the conversion of N-carbamyl-{\ss}-alanine and N-carbamyl-{\ss}-aminoisobutyric acid to {\ss}-alanine and {\ss}-aminoisobutyric acid, ammonia and CO 2. To date, only five genetically confirmed patients with a complete {\ss}-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 11 newly identified {\ss}-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-{\ss}-alanine and N-carbamyl-{\ss}-aminoisobutyric acid in urine and plasma. Analysis of UPB1, encoding {\ss}-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 {\ss}-ureidopropionase proteins with significantly decreased activity. Analysis of a homology model of human {\ss}-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 {\ss}-ureidopropionase patients, indicating that {\ss}-ureidopropionase deficiency may be more common than anticipated.",
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Van Kuilenburg, ABP, Dobritzsch, D, Meijer, J, Krumpel, M, Selim, LA, Rashed, MS, Assmann, B, Meinsma, R, Lohkamp, B, Ito, T, Abeling, NGGM, Saito, K, Eto, K, Smitka, M, Engvall, M, Zhang, C, Xu, W, Zoetekouw, L & Hennekam, RCM 2012, 'ß-Ureidopropionase deficiency: Phenotype, genotype and protein structural consequences in 16 patients', Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1822, no. 7, pp. 1096-1108. https://doi.org/10.1016/j.bbadis.2012.04.001

ß-Ureidopropionase deficiency : Phenotype, genotype and protein structural consequences in 16 patients. / Van Kuilenburg, André B.P.; Dobritzsch, Doreen; Meijer, Judith; Krumpel, Michael; Selim, Laila A.; Rashed, Mohamed S.; Assmann, Birgit; Meinsma, Rutger; Lohkamp, Bernhard; Ito, Tetsuya; Abeling, Nico G.G.M.; Saito, Kayoko; Eto, Kaoru; Smitka, Martin; Engvall, Martin; Zhang, Chunhua; Xu, Wang; Zoetekouw, Lida; Hennekam, Raoul C.M.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1822, No. 7, 01.07.2012, p. 1096-1108.

Research output: Contribution to journalArticle

TY - JOUR

T1 - ß-Ureidopropionase deficiency

T2 - Phenotype, genotype and protein structural consequences in 16 patients

AU - Van Kuilenburg, André B.P.

AU - Dobritzsch, Doreen

AU - Meijer, Judith

AU - Krumpel, Michael

AU - Selim, Laila A.

AU - Rashed, Mohamed S.

AU - Assmann, Birgit

AU - Meinsma, Rutger

AU - Lohkamp, Bernhard

AU - Ito, Tetsuya

AU - Abeling, Nico G.G.M.

AU - Saito, Kayoko

AU - Eto, Kaoru

AU - Smitka, Martin

AU - Engvall, Martin

AU - Zhang, Chunhua

AU - Xu, Wang

AU - Zoetekouw, Lida

AU - Hennekam, Raoul C.M.

PY - 2012/7/1

Y1 - 2012/7/1

N2 - ß-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyzes the conversion of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid to ß-alanine and ß-aminoisobutyric acid, ammonia and CO 2. To date, only five genetically confirmed patients with a complete ß-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 11 newly identified ß-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-ß-alanine and N-carbamyl-ß-aminoisobutyric acid in urine and plasma. Analysis of UPB1, encoding ß-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 ß-ureidopropionase proteins with significantly decreased activity. Analysis of a homology model of human ß-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 ß-ureidopropionase patients, indicating that ß-ureidopropionase deficiency may be more common than anticipated.

AB - ß-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyzes the conversion of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid to ß-alanine and ß-aminoisobutyric acid, ammonia and CO 2. To date, only five genetically confirmed patients with a complete ß-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 11 newly identified ß-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-ß-alanine and N-carbamyl-ß-aminoisobutyric acid in urine and plasma. Analysis of UPB1, encoding ß-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 ß-ureidopropionase proteins with significantly decreased activity. Analysis of a homology model of human ß-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 ß-ureidopropionase patients, indicating that ß-ureidopropionase deficiency may be more common than anticipated.

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