Novel STAT1 Variants in Japanese Patients with Isolated Mendelian Susceptibility to Mycobacterial Diseases
Novel STAT1 Variants in Japanese Patients with Isolated Mendelian Susceptibility to Mycobacterial Diseases
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DOI：
10.1007/s10875-022-01396-1
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发表时间：
2022-11
影响因子：
9.1
通讯作者：
Rintaro Ono;M. Tsumura;S. Shima;Yusuke Matsuda;K. Gotoh;Yurina Miyata;Y. Yoto;Dan Tomomasa;Takanori Utsumi;H. Ohnishi;Zenichiro Kato;N. Ishiwada;A. Ishikawa;T. Wada;H. Uhara;R. Nishikomori;D. Hasegawa;S. Okada;H. Kanegane
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作者：
Rintaro Ono;M. Tsumura;S. Shima;Yusuke Matsuda;K. Gotoh;Yurina Miyata;Y. Yoto;Dan Tomomasa;Takanori Utsumi;H. Ohnishi;Zenichiro Kato;N. Ishiwada;A. Ishikawa;T. Wada;H. Uhara;R. Nishikomori;D. Hasegawa;S. Okada;H. Kanegane
目的：常染色体显性遗传性(AD)孟德尔人对分枝杆菌病(MSMD)的易感性与杂合性显性-阴性(DN)STAT1变异有关。本文描述了来自日本4个家系的8例MSMD病例。方法利用从全血中提取的基因组DNA进行免疫相关基因的先天错误测序。利用Sanger测序对鉴定出的变异体进行验证。结果患者1.1为一名20个月大的男孩，患有卡介苗(BCG)引起的多发性骨髓炎和椎旁脓肿。尽管椎旁脓肿对抗分枝杆菌药物无效，但加用干扰素-γ和脓肿引流是有效的。耐人寻味的是，他的母亲(1.2号患者)的临床病程平淡无奇，除了成年后对治疗有反应的结核性脊柱炎。患者2.1是一名8个月大的男婴，患有卡介苗引起的淋巴结节和肺结节。他对抗分枝杆菌药物反应良好。他的母亲(患者2.2)很健康。患者3.1是一名11岁女孩，疑似皮肤结核。她的哥哥(3.2名患者)患有卡介苗病，但他们的母亲(3.3名患者)很健康。患者4是一名8个月大的女孩，与卡介苗接种相关的左腋窝和锁骨上淋巴结病。家系1、2和3分别在STAT1中存在新的杂合变异(V642F、R588C和R649G)。家系4此前曾报道过杂合变异(Q463H)。在干扰素-γ刺激后，在STAT1缺陷细胞中进行的荧光素酶报告分析证实，这些变体是功能丧失的。结论本研究共鉴定了4例MSMD家系受试者，其中3例为新变异体，1例为已知变异体。AD STAT1缺乏症可能在日本卡介苗相关性MSMD患者中普遍存在。
PurposeHeterozygous dominant-negative (DN)STAT1variants are responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD). In this paper, we describe eight MSMD cases from four kindreds in Japan.MethodsAn inborn error of immunity-related gene panel sequencing was performed using genomic DNA extracted from whole blood samples. The identified variants were validated using Sanger sequencing. Functional analysis was evaluated with a luciferase reporter assay and co-transfection assay in STAT1-deficient cells.ResultsPatient 1.1 was a 20-month-old boy with multifocal osteomyelitis and paravertebral abscesses caused byMycobacterium bovisbacillus Calmette-Guérin (BCG). Although the paravertebral abscess was refractory to antimycobacterial drugs, the addition of IFN-γ and drainage of the abscess were effective. Intriguingly, his mother (patient 1.2) showed an uneventful clinical course except for treatment-responsive tuberculous spondylitis during adulthood. Patient 2.1 was an 8-month-old boy with lymphadenopathy and lung nodules caused by BCG. He responded well to antimycobacterial drugs. His mother (patient 2.2) was healthy. Patient 3.1 was a 11-year-old girl with suspected skin tuberculosis. Her brother (patient 3.2) had BCG-osis, but their mother (patient 3.3) was healthy. Patient 4 was an 8-month-old girl with left axillary and supraclavicular lymphadenopathy associated with BCG vaccination. Kindreds 1, 2, and 3 were shown to have novel heterozygous variants (V642F, R588C, and R649G) inSTAT1, respectively. Kindred 4 had previously reported heterozygous variants (Q463H). A luciferase reporter assay in STAT1-deficient cells followed by IFN-γ stimulation confirmed that these variants are loss-of-function. In addition, with co-transfection assay, we confirmed all of these variants had DN effect on WTSTAT1.ConclusionFour kindred MSMD subjects with 3 novel variants and 1 known variant inSTAT1were identified in this study. AD STAT1 deficiency might be prevalent in Japanese patients with BCG-associated MSMD.