A new mouse model of mild ornithine transcarbamylase deficiency (spf-j) displays cerebral amino acid perturbations at baseline and upon systemic immune activation.
A new mouse model of mild ornithine transcarbamylase deficiency (spf-j) displays cerebral amino acid perturbations at baseline and upon systemic immune activation.
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DOI：
10.1371/journal.pone.0116594
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
McGuire PJ
中科院分区：
文献类型：
--
作者：
Tarasenko TN;Rosas OR;Singh LN;Kristaponis K;Vernon H;McGuire PJ
鸟氨酸转氨甲酰酶缺乏症（OTCD，OMIM# 311250）是一种遗传性X连锁尿素循环障碍，其特征在于高氨血症和乳清酸尿症。在这份报告中，我们描述了一种新的OTCD动物模型，该模型由小鼠Otc基因（c.240T>A，p.K80N）的自发突变引起。鸟氨酸转氨甲酰酶外显子3中的这种颠换导致正常水平的mRNA和低水平的成熟蛋白，并且与也在患有迟发型OTCD的单个患者中描述的突变同源。发现spf-J具有较高的残余酶活性，具有正常的血浆氨和乳清酸。基线血浆氨基酸谱与轻度OTCD一致：谷氨酰胺升高，瓜氨酸和精氨酸降低。与WT相比，spf-J显示在用聚肌苷酸：聚胞苷酸免疫激发后脑氨基酸的基线升高和消耗。我们的研究结果表明，轻度spf-J突变构成了一种新的小鼠模型，适用于轻度OTCD的机制研究和人类近端尿素循环功能障碍为特征的急性失代偿期间脑病理生理学的探索。
Ornithine transcarbamylase deficiency (OTCD, OMIM# 311250) is an inherited X-linked urea cycle disorder that is characterized by hyperammonemia and orotic aciduria. In this report, we describe a new animal model of OTCD caused by a spontaneous mutation in the mouse Otc gene (c.240T>A, p.K80N). This transversion in exon 3 of ornithine transcarbamylase leads to normal levels of mRNA with low levels of mature protein and is homologous to a mutation that has also been described in a single patient affected with late-onset OTCD. With higher residual enzyme activity, spf-J were found to have normal plasma ammonia and orotate. Baseline plasma amino acid profiles were consistent with mild OTCD: elevated glutamine, and lower citrulline and arginine. In contrast to WT, spf-J displayed baseline elevations in cerebral amino acids with depletion following immune challenge with polyinosinic:polycytidylic acid. Our results indicate that the mild spf-J mutation constitutes a new mouse model that is suitable for mechanistic studies of mild OTCD and the exploration of cerebral pathophysiology during acute decompensation that characterizes proximal urea cycle dysfunction in humans.
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影响因子：
3.7
作者：
Singh, Larry N.;Hannenhalli, Sridhar
通讯作者：
Hannenhalli, Sridhar
影响因子：
3.1
作者：
D'Apolito, Oceania;Garofalo, Daniela;Corso, Gaetano
通讯作者：
Corso, Gaetano
影响因子：
4
作者：
Matsuda, I;Matsuura, T;Yoshino, M
通讯作者：
Yoshino, M
DOI：
10.1016/j.bbrc.2003.07.012
发表时间：
2004-01-09
影响因子：
3.1
作者：
Meijer, AJ;Dubbelhuis, PF
通讯作者：
Dubbelhuis, PF
影响因子：
5.1
作者：
Summar, M;Tuchman, M
通讯作者：
Tuchman, M