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

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)216-222
Number of pages7
JournalMolecular Genetics and Metabolism
Volume122
Issue number4
DOIs
Publication statusPublished - 01-12-2017

Fingerprint

dihydropyrimidinase
Structural integrity
Catalyst activity
Mutation
Proteins
Infantile Spasms
Enzyme Stability
Dihydropyrimidinase Deficiency
Ethnic Groups
Point Mutation
Functional analysis
Atrophy
Molecular Biology
Catalytic Domain
Enzymes
Urine

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

Nakajima, Yoko ; Meijer, Judith ; Dobritzsch, Doreen ; Ito, Tetsuya ; Zhang, Chunhua ; Wang, Xu ; Watanabe, Yoriko ; Tashiro, Kyoko ; Meinsma, Rutger ; Roelofsen, Jeroen ; Zoetekouw, Lida ; van Kuilenburg, André B.P. / Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity. In: Molecular Genetics and Metabolism. 2017 ; Vol. 122, No. 4. pp. 216-222.
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abstract = "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.",
author = "Yoko Nakajima and Judith Meijer and Doreen Dobritzsch and Tetsuya Ito and Chunhua Zhang and Xu Wang and Yoriko Watanabe and Kyoko Tashiro and Rutger Meinsma and Jeroen Roelofsen and Lida Zoetekouw and {van Kuilenburg}, {Andr{\'e} B.P.}",
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Nakajima, Y, Meijer, J, Dobritzsch, D, Ito, T, Zhang, C, Wang, X, Watanabe, Y, Tashiro, K, Meinsma, R, Roelofsen, J, Zoetekouw, L & van Kuilenburg, ABP 2017, 'Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity', Molecular Genetics and Metabolism, vol. 122, no. 4, pp. 216-222. https://doi.org/10.1016/j.ymgme.2017.10.003

Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity. / Nakajima, Yoko; Meijer, Judith; Dobritzsch, Doreen; Ito, Tetsuya; Zhang, Chunhua; Wang, Xu; Watanabe, Yoriko; Tashiro, Kyoko; Meinsma, Rutger; Roelofsen, Jeroen; Zoetekouw, Lida; van Kuilenburg, André B.P.

In: Molecular Genetics and Metabolism, Vol. 122, No. 4, 01.12.2017, p. 216-222.

Research output: Contribution to journalArticle

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T1 - Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity

AU - Nakajima, Yoko

AU - Meijer, Judith

AU - Dobritzsch, Doreen

AU - Ito, Tetsuya

AU - Zhang, Chunhua

AU - Wang, Xu

AU - Watanabe, Yoriko

AU - Tashiro, Kyoko

AU - Meinsma, Rutger

AU - Roelofsen, Jeroen

AU - Zoetekouw, Lida

AU - van Kuilenburg, André B.P.

PY - 2017/12/1

Y1 - 2017/12/1

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