Identification and functional analysis of three novel genetic variants resulting in premature termination codons in three unrelated patients with hereditary antithrombin deficiency
Identification and functional analysis of three novel genetic variants resulting in premature termination codons in three unrelated patients with hereditary antithrombin deficiency
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导致三名无关的遗传性抗凝血酶缺乏症患者过早终止密码子的三种新遗传变异的鉴定和功能分析
DOI：
10.1007/s12185-022-03509-3
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发表时间：
2022
影响因子：
2.1
通讯作者：
Morishita Eriko
中科院分区：
文献类型：
--
作者：
Imai Yuta;Nagaya Satomi;Araiso Yuhei;Meguro-Horike Makiko;Togashi Tomoki;Ohmori Kensho;Makita Yuka;Sato Eiichi;Yujiri Toshiaki;Nagamori Yuta;Horike Shin-ichi;Watanabe Atsushi;Morishita Eriko
遗传性抗凝血酶（AT）缺乏症是一种常染色体显性遗传性血栓形成倾向。在三个遗传性I型AT缺陷的家系中，我们在每个患者的编码AT的开放阅读框架中鉴定了新的变异体c.126 delC（p.Lys43Serfs*7）、c.165 C> G（p.Tyr55*）和c.546 delA（p.Lys182Asnfs*102）。这些异常变体中的每一种都导致AT蛋白合成的过早终止。为了研究这些异常变体是否参与I型AT缺乏症的发病机制，我们分析了HEK 293细胞中这些变体的功能。Western blot分析和免疫荧光显微镜结果显示，所有异常变异体均在细胞内表达，但p.Lys43Serfs*7和p.Tyr55* 蛋白在细胞内聚集。在用过的培养基中未检测到这三种变体，表明这些新变体影响蛋白质分泌。总之，我们认为，AT编码基因中的这些变体在细胞中被翻译，但形成异常蛋白，形成聚集体和/或抑制分泌。这些结果为I型AT缺乏症的新机制和潜在的治疗方法提供了见解。
Hereditary antithrombin (AT) deficiency is an autosomal dominant inherited thrombophilia. In three pedigrees of hereditary type I AT deficiency, we identified novel variants c.126delC (p.Lys43Serfs*7), c.165C > G (p.Tyr55*), and c.546delA (p.Lys182Asnfs*102) in the open reading frame encoding AT in each patient. Each of these aberrant variants leads to premature termination of AT protein synthesis. To investigate whether these abnormal variants are involved in the pathogenesis of type I AT deficiency, we analyzed the function of these variants in HEK293 cells. Results of western blot analysis and immunofluorescence microscopy showed that all abnormal variants were expressed intracellularly, but p.Lys43Serfs*7 and p.Tyr55*protein were aggregated in the cells. These three variants were not detected in the spent culture medium, indicating that these novel variants affect protein secretion. In summary, we suggest that these variants in the AT-encoding gene are translated in the cell, but form abnormal proteins that form aggregates and/or inhibit secretion. These results provide insight into novel mechanisms of type I AT deficiency and potential therapies for the condition.
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影响因子：
11.1
作者：
Popp MW;Maquat LE
通讯作者：
Maquat LE
抗凝血酶缺乏症的分子遗传学
影响因子：
7.4
作者：
Robin J. Olid;David A.Lane;S. Thein
通讯作者：
S. Thein
抗凝血酶、蛋白 C 或蛋白 S 缺乏的无症状携带者静脉血栓栓塞的发生率：一项前瞻性队列研究。
影响因子：
20.3
作者：
B. Sanson;P. Simioni;D. Tormene;M. Moia;P. Friederich;M. Huisman;P. Prandoni;A. Bura;L. Rejtő;P. Wells;P. Mannucci;A. Girolami;H. Büller;M. Prins
通讯作者：
M. Prins
由 29 个核苷酸缺失引起的 ADAMTS13 基因中无义介导的 mRNA 衰减
影响因子：
10.1
作者：
I. Garagiola;C. Valsecchi;Silvia Lavoretano;H. Oren;M. Bohm;F. Peyvandi
通讯作者：
F. Peyvandi
遗传性 AT 缺陷的两例病例报告：一种新的移码突变和使用两种方法检测到的包括所有七个外显子的大缺失。
影响因子：
2.1
作者：
Sekiya A;Asakura H;et al.
通讯作者：
et al.