Full-length antithrombin frameshift variant with aberrant C-terminus causes endoplasmic reticulum retention with a dominant-negative effect.
Full-length antithrombin frameshift variant with aberrant C-terminus causes endoplasmic reticulum retention with a dominant-negative effect.
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DOI：
10.1172/jci.insight.161430
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发表时间：
2022-10-10
期刊：
影响因子：
8
通讯作者：
Corral, Javier
中科院分区：
文献类型：
--
作者：
Bravo-Perez, Carlos;Toderici, Mara;Chambers, Joseph E.;Martinez-Menarguez, Jose A.;Garrido-Rodriguez, Pedro;Perez-Sanchez, Horacio;De La Morena-Barrio, Belen;Padilla, Jose;Minano, Antonia;Cifuentes-Riquelme, Rosa;Vicente, Vicente;Lozano, Maria L.;Marciniak, Stefan J.;Eugenia de la Morena-Barrio, Maria;Corral, Javier
抗凝血酶是一种主要的内源性抗凝剂，是一种丝氨酸蛋白酶抑制剂（serpin）。我们的特点涉及C-末端抗凝血酶的变异体的生物学和临床影响。我们对来自444名确诊为抗凝血酶缺乏症的无关个体的C末端抗凝血酶变异患者进行了全面的分子、细胞和临床表征。我们确定了17例携带12个C端变异的患者，其中5例有p.Arg445Serfs*17缺失。其中5个错义突变体引起了定性缺陷，7个（包括4个插入-缺失突变体）引起了严重的定量缺陷，特别是p.Arg445Serfs*17（抗凝血酶<40%）。该+1移码变体具有与WT抗凝血酶相似的分子大小，但具有不同的C-末端。形态学和共转染实验表明，重组p.Arg445Serfs*17被保留在内质网，并对WT抗凝血酶具有显性负效应。不同的1+移码，异常的C-末端变体的表征表明，蛋白质分泌由移码位点决定。在异常的C-末端引入Pro441，由5个有效分泌的变体共享，部分挽救了p.Arg445Serfs*17的分泌。抗凝血酶C端突变体具有显著的异质性，与变异类型和定位有关。由1+移码引起的异常C-末端变体，其大小与WT抗凝血酶相似，可能分泌或不分泌，取决于移码位点。这些遗传变化的严重临床表型与其显性负效应一致。
Antithrombin, a major endogenous anticoagulant, is a serine protease inhibitor (serpin). We characterized the biological and clinical impact of variants involving C-terminal antithrombin. We performed comprehensive molecular, cellular, and clinical characterization of patients with C-terminal antithrombin variants from a cohort of 444 unrelated individuals with confirmed antithrombin deficiency. We identified 17 patients carrying 12 C-terminal variants, 5 of whom had the p.Arg445Serfs*17 deletion. Five missense variants caused qualitative deficiency, and 7, including 4 insertion-deletion variants, induced severe quantitative deficiency, particularly p.Arg445Serfs*17 (antithrombin <40%). This +1 frameshift variant had a molecular size similar to that of WT antithrombin but possessed a different C-terminus. Morphologic and cotransfection experiments showed that recombinant p.Arg445Serfs*17 was retained at the endoplasmic reticulum and had a dominant-negative effect on WT antithrombin. Characterization of different 1+ frameshift, aberrant C-terminal variants revealed that protein secretion was determined by frameshift site. The introduction of Pro441 in the aberrant C-terminus, shared by 5 efficiently secreted variants, partially rescued p.Arg445Serfs*17 secretion. C-terminal antithrombin mutants have notable heterogeneity, related to variant type and localization. Aberrant C-terminal variants caused by 1+ frameshift, with similar size as WT antithrombin, may be secreted or not, depending on frameshift site. The severe clinical phenotypes of these genetic changes are consistent with their dominant-negative effects.
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影响因子：
10.4
作者：
Hernandez-Espinosa, D.;Minano, A.;Corral, J.
通讯作者：
Corral, J.
DOI：
10.1073/pnas.1603386113
发表时间：
2016-06-07
影响因子：
11.1
作者：
Chandrasekhar, Kshama;Ke, Haiping;Hebert, Daniel N.
通讯作者：
Hebert, Daniel N.
影响因子：
12.8
作者：
David, D;Ribeiro, S;Crespo, F
通讯作者：
Crespo, F
影响因子：
4.1
作者：
Arii, Y;Hirose, M
通讯作者：
Hirose, M
DOI：
10.1161/01.atv.14.12.1958
发表时间：
1994-12-01
期刊：
ARTERIOSCLEROSIS AND THROMBOSIS
影响因子：
--
作者：
EMMERICH, J;VIDAUD, D;AIACH, M
通讯作者：
AIACH, M