Asparagine Synthetase Deficiency causes reduced proliferation of cells under conditions of limited asparagine.
Asparagine Synthetase Deficiency causes reduced proliferation of cells under conditions of limited asparagine.
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DOI：
10.1016/j.ymgme.2015.08.007
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发表时间：
2015-11
影响因子：
3.8
通讯作者：
Kirk, Edwin P.
中科院分区：
文献类型：
--
作者：
Palmer, Elizabeth Emma;Hayner, Jaclyn;Sachdev, Rani;Cardamone, Michael;Kandula, Tejaswi;Morris, Paula;Dias, Kerith-Rae;Tao, Jiang;Miller, David;Zhu, Ying;Macintosh, Rebecca;Dinger, Marcel E.;Cowley, Mark J.;Buckley, Michael F.;Roscioli, Tony;Bye, Ann;Kilberg, Michael S.;Kirk, Edwin P.
天冬酰胺合成酶缺乏症是最近描述的严重智力残疾、显著进行性脑萎缩和可变癫痫发作障碍的原因。迄今为止，解释潜在病理生理学的功能数据有限。我们报告了一个新的病例与复合杂合突变的ASNS基因（NM_183356.3：c。[866G>C]; [1010C>T]）。这两种变体都改变了进化上保守的氨基酸，并且基于计算机模拟蛋白质建模预测为致病性的，该蛋白质建模表明ASNS酶的关键ATP结合位点被破坏。在患者成纤维细胞中，ASNS表达以及蛋白质和mRNA稳定性不受这些变体的影响。然而，与亲本和野生型成纤维细胞相比，当在天冬酰胺限制的生长培养基中培养时，患者成纤维细胞的增殖显著降低。限制天冬酰胺复制了血脑屏障内的生理学，限制了饮食来源的天冬酰胺的转移，导致神经元细胞依赖于ASNS酶的细胞内天冬酰胺合成。这些功能研究提供了对与天冬酰胺合成酶缺乏相关的急剧进行性脑萎缩的潜在病理生理学的深入了解。
Asparagine Synthetase Deficiency is a recently described cause of profound intellectual disability, marked progressive cerebral atrophy and variable seizure disorder. To date there has been limited functional data explaining the underlying pathophysiology. We report a new case with compound heterozygous mutations in the ASNS gene (NM_183356.3:c. [866G>C]; [1010C>T]). Both variants alter evolutionarily conserved amino acids and were predicted to be pathogenic based on in silico protein modelling that suggests disruption of the critical ATP binding site of the ASNS enzyme. In patient fibroblasts, ASNS expression as well as protein and mRNA stability are not affected by these variants. However, there is markedly reduced proliferation of patient fibroblasts when cultured in asparagine-limited growth medium, compared to parental and wild type fibroblasts. Restricting asparagine replicates the physiology within the blood–brain-barrier, with limited transfer of dietary derived asparagine, resulting in reliance of neuronal cells on intracellular asparagine synthesis by the ASNS enzyme. These functional studies offer insight into the underlying pathophysiology of the dramatic progressive cerebral atrophy associated with Asparagine Synthetase Deficiency.
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影响因子：
9.5
作者：
Thorvaldsdóttir H;Robinson JT;Mesirov JP
通讯作者：
Mesirov JP
影响因子：
2.9
作者：
Larsen, TM;Boehlein, SK;Rayment, I
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影响因子：
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van der Crabben, S. N.;Verhoeven-Duif, N. M.;de Koning, T. J.
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de Koning, T. J.
影响因子：
9.3
作者：
Kilberg, Michael S.;Balasubramanian, Mukundh;Shan, Jixiu
通讯作者：
Shan, Jixiu
影响因子：
5.8
作者：
Arnold, K;Bordoli, L;Schwede, T
通讯作者：
Schwede, T