Molecular and Genetic Mechanisms of Factor XIII A Subunit Deficiency
Molecular and Genetic Mechanisms of Factor XIII A Subunit Deficiency
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XIII A 因子亚基缺陷的分子和遗传机制
DOI：
10.1055/s-2000-9795
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发表时间：
2000
影响因子：
5.7
通讯作者：
Nobumasa Takahashi
中科院分区：
文献类型：
--
作者：
A. Ichinose;M. Souri;T. Izumi;Nobumasa Takahashi
因子XIII是血浆转氨酶的酶原。血浆中的因子XIII是通过非共价键结合在一起的四聚体（A2 B2），并且A亚基包含活性位点。最近，A亚基的三维结构已经通过X射线晶体学确定。为了了解因子XIII分子的结构-功能关系及其在因子XIII缺乏症中的临床意义，我们描述了其遗传缺陷并仔细检查了其基因产物，包括mRNA和蛋白质水平。在证明A亚基缺乏的病例中，已鉴定出各种错义和无义突变（Arg 260-Cys、Tyr 283-Cys、Gly 562-Arg）以及缺失/插入（伴或不伴框外移位/提前终止和剪接异常）（伴464 Stop的4-bp缺失、伴外显子IV跳跃的外显子IV/内含子D边界处的T插入、外显子I/内含子A边界处的20-bp缺失）。在某些情况下，A亚基mRNA水平严重降低。它们的分子和细胞基础也已经通过在哺乳动物细胞中的表达实验和分子建模进行了探索。在大多数情况下，受损的折叠和/或构象变化的突变A亚基导致细胞内和细胞外的不稳定性，这是负责在患者中的A亚基缺陷。
Factor XIII is a proenzyme for a plasma transglutaminase. Factor XIII in plasma is a tetramer (A2B2) held together by noncovalent bonds, and the A subunit contains the active site. Recently, the three-dimensional structure of the A subunit has been determined by x-ray crystallography. To understand the structure-function relationships of the factor XIII molecule and its clinical implications in factor XIII deficiency, we characterized its genetic defects and closely examined its gene products, including mRNA and protein levels. A variety of missense and nonsense mutations (Arg260-Cys, Tyr283-Cys, Gly562-Arg) and deletions/insertions with or without out-of-frame shift/premature termination and splicing abnormalities (4-bp deletion with 464Stop, T insertion at the exon IV/intron D boundary with exon IV-skipping, 20-bp deletion at the exon I/intron A boundary) has been identified in cases demonstrating A subunit deficiency. In some cases, the A subunit mRNA levels were severely reduced. Their molecular and cellular bases have also been explored by expression experiments in mammalian cells and by molecular modeling. In most cases, impaired folding and/or conformational changes of the mutant A subunits lead to both intra- and extracellular instability, which is responsible for the A subunit deficiency in the patients.