Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity

Yoko Nakajima, Judith Meijer, Doreen Dobritzsch, Tetsuya Ito, Chunhua Zhang, Xu Wang, Yoriko Watanabe, Kyoko Tashiro, Rutger Meinsma, Jeroen Roelofsen, Lida Zoetekouw, André B.P. van Kuilenburg

研究成果: Article査読

8 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)216-222
ページ数7
ジャーナルMolecular Genetics and Metabolism
122
4
DOI
出版ステータスPublished - 12-2017

All Science Journal Classification (ASJC) codes

  • 内分泌学、糖尿病および代謝内科学
  • 生化学
  • 分子生物学
  • 遺伝学
  • 内分泌学

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