D-Amino acid oxidase deficiency is caused by a large deletion in the Dao gene in LEA rats
D-Amino acid oxidase deficiency is caused by a large deletion in the Dao gene in LEA rats
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DOI：
10.1016/j.bbapap.2020.140463
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发表时间：
2020-09-01
影响因子：
3.2
通讯作者：
Okamura，Tadashi
中科院分区：
文献类型：
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作者：
Shimizu，Yukiko;Ishii，Chiharu;Okamura，Tadashi
D-氨基酸是l-氨基酸的对映体，被认为是生理活性分子和疾病的潜在生物标志物。D-氨基酸氧化酶(DAO)催化d-氨基酸的氧化脱氨反应，广泛存在于从酵母到人类的各种生物体中。以往的研究表明，LEA大鼠缺乏DAO活性，其组织中d-Ser和d-Ala水平显著升高，提示LEA基因组中存在一个导致DAO活性缺失的突变位点(LDO)。序列分析发现，缺失断裂点位于道氏基因内含子4-5和Svopgene的内含子1-2，导致54.1kb的缺失，包括道氏基因的外显子5-12和Svopgene的外显子2-16。我们开发了一种新的同源基因大鼠品系F344-道道，该品系含有LEA大鼠在F344遗传背景上的道道突变。与亲本F344株相比，F344-道型的d-Ala在大脑和小脑中均显著升高，而小脑中d-Ser的含量增加，而d-Ala、d-Ser、d-Pro和d-Leu的含量在F344-道型中也显著升高。F344-Daoldaorats代表了一个新的模型系统，它将有助于阐明d-氨基酸在体内的生理功能。(203字)。
d-Amino acids, enantiomers ofl-amino acids, are increasingly recognized as physiologically active molecules as well as potential biomarkers for diseases.d-Amino acid oxidase (DAO) catalyzes the oxidative deamination ofd-amino acids and is present in a wide variety of organisms from yeasts to humans. Previous studies indicated that LEA rats lacked DAO activity, and levels ofd-Ser andd-Ala were markedly increased in their tissues, suggesting a mutated locus responsible for the lack of Dao activity (ldao) existed in the LEA genome. Sequence analysis identified deletion breakpoints located in intron 4–5 of theDaogene and intron 1–2 of theSvopgene, resulting in a 54.1-kb deletion which encompassed exons 5–12 of theDaogene and exons 2–16 of theSvopgene. We developed a novel congenic rat strain, F344-Daoldao, harboring theDaoldaomutation from LEA rats delivered onto the F344 genetic background. Compared to the parental F344 strain, in F344-Daoldaoratsd-Ala was markedly increased in both cerebrum and cerebellum, whiled-Ser content was increased in cerebellum but not cerebrum.d-Ala,d-Ser,d-Pro andd-Leu levels were also elevated in F344-Daoldaoplasma. F344-Daoldaorats represent a novel model system that will aid in elucidating the physiological functions ofd-amino acidsin vivo. (203 words).