Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity
Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity
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DOI：
10.1016/j.ymgme.2017.10.003
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发表时间：
2017-12-01
影响因子：
3.8
通讯作者：
van Kuilenburg, Andre B. P.
中科院分区：
文献类型：
--
作者：
Nakajima, Yoko;Meijer, Judith;van Kuilenburg, Andre B. P.
二氢嘧啶酶（DHP）是嘧啶降解途径的第二种酶，催化5,6-二氢尿嘧啶和5,6-二氢胸腺嘧啶的开环。迄今为止，仅报道了 31 例经基因证实的 DHP 缺乏症患者，因此 DHP 缺乏症患者的临床、生化和遗传谱在很大程度上仍不清楚。在这里，我们发现 4 名新发现的 DHP 缺乏患者的尿液中 5,6-二氢尿嘧啶和 5,6-二氢胸腺嘧啶水平显着升高，并且临床表现高度可变，从无症状到婴儿痉挛、白质减少和脑萎缩。 DHP 基因 (DPYS) 分析显示存在 8 个变体，其中包括 4 个新的/罕见的错义变体和 1 个新的缺失。携带p.M250I、p.H295R、p.Q334R、p.T418I和p.R490H变体的重组表达的DHP突变体的功能分析显示残余DHP活性分别为2.0%、9.8%、9.7%、64%和0.3%。人 DHP 的晶体结构表明，所有点突变都可能导致形成活性位点的环重排，主要影响底物结合和酶的稳定性。所发现的突变在东亚人和日本人群中更为普遍的观察表明，DHP 缺乏症在这些种族群体中可能比预期更常见。
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.