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Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. (Dobritzsch)ORCID iD: 0000-0002-1822-6513
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2017 (English)In: Molecular Genetics and Metabolism, ISSN 1096-7192, E-ISSN 1096-7206, Vol. 122, no 4, p. 216-222Article in journal (Refereed) Published
Abstract [en]

Dihydropyrimidinase (DHP) is the second enzyme of the pyrimidine degradation pathway and catalyzes the ring opening of 5,6-dihydrouracil and 5,6-dihydrothymine. To date, only 31 genetically confirmed patients with a DHP deficiency have been reported and the clinical, biochemical and genetic spectrum of DHP deficient patients is, therefore, still largely unknown. Here, we show that 4 newly identified DHP deficient patients presented with strongly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in urine and a highly variable clinical presentation, ranging from asymptomatic to infantile spasm and reduced white matter and brain atrophy. Analysis of the DHP gene (DPYS) showed the presence of 8 variants including 4 novel/rare missense variants and one novel deletion. Functional analysis of recombinantly expressed DHP mutants carrying the p.M250I, p.H295R, p.Q334R, p.T418I and the p.R490H variant showed residual DHP activities of 2.0%, 9.8%, 9.7%, 64% and 0.3%, respectively. The crystal structure of human DHP indicated that all point mutations were likely to cause rearrangements of loops shaping the active site, primarily affecting substrate binding and stability of the enzyme. The observation that the identified mutations were more prevalent in East Asians and the Japanese population indicates that DHP deficiency may be more common than anticipated in these ethnic groups.

Place, publisher, year, edition, pages
2017. Vol. 122, no 4, p. 216-222
Keywords [en]
Crystal structure, DPYS, Dihydropyrimidinase, Functional and structural protein analysis, Patients
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-338128DOI: 10.1016/j.ymgme.2017.10.003ISI: 000418879000010PubMedID: 29054612OAI: oai:DiVA.org:uu-338128DiVA, id: diva2:1171465
Available from: 2018-01-08 Created: 2018-01-08 Last updated: 2018-02-02Bibliographically approved

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