Kato Io, Takagi Yuki, Ando Yumi, Nakamura Yuki, Murata Moe, Takagi Akira, Murate Takashi, Matsushita Tadashi, Nakashima Tadaaki, Kojima Tetsuhito
Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-Minami, Higashi-ku, Nagoya, 461-8673, Japan.
Int J Hematol. 2014 Aug;100(2):200-5. doi: 10.1007/s12185-014-1596-9. Epub 2014 Jun 3.
Hereditary antithrombin (AT) deficiency is an autosomal dominant thrombophilic disorder caused by SERPINC1 abnormality. In the present study, we analyzed SERPINC1 in a Japanese patient with AT deficiency and autoimmune disease-like symptoms. Direct sequencing and multiplex ligation-dependent probe amplification revealed that the patient was hemizygous for the entire SERPINC1 deletion. Single nucleotide polymorphism genotyping, gene dose measurement, and long-range polymerase chain reaction (PCR) followed by mapping PCR and direct sequencing of the long-range PCR products revealed that the patient had an approximately 111-kb gene deletion from exon 2 of ZBTB37 to intron 5 of RC3H1, including the entire SERPINC1 in chromosome 1. We also found a 7-bp insertion of an unknown origin in the breakpoint, which may be a combination of three parts with a few base-pair microhomologies, resulting from a replication-based process known as 'fork stalling and template switching'. Because RC3H1, which encodes the protein roquin is involved in the repression of self-immune responses, the autoimmune disease-like symptoms of the patient may have resulted from this gene defect. In conclusion, we identified an entire SERPINC1 deletion together with a large deletion of RC3H1 in an AT-deficient patient with autoimmune disease-like symptoms.
遗传性抗凝血酶（AT）缺乏症是一种由SERPINC1异常引起的常染色体显性遗传性易栓症。在本研究中，我们分析了一名患有AT缺乏症及自身免疫性疾病样症状的日本患者的SERPINC1基因。直接测序和多重连接依赖探针扩增结果显示，该患者为SERPINC1基因全缺失的半合子。单核苷酸多态性基因分型、基因剂量测定以及长程聚合酶链反应（PCR），随后对长程PCR产物进行定位PCR和直接测序，结果表明该患者在1号染色体上存在一个约111 kb的基因缺失，从ZBTB37的外显子2到RC3H1的内含子5，包括整个SERPINC1基因。我们还在断点处发现了一个来源不明的7 bp插入片段，它可能是由三个具有少量碱基对微同源性的部分组合而成，这是一种基于复制的过程，即“叉停滞和模板转换”所导致的结果。由于编码roquin蛋白的RC3H1参与自身免疫反应的抑制，该患者的自身免疫性疾病样症状可能是由这一基因缺陷引起的。总之，我们在一名患有自身免疫性疾病样症状的AT缺乏症患者中鉴定出了整个SERPINC1基因缺失以及RC3H1的大片段缺失。
