Novel STAT1 Variants in Japanese Patients with Isolated Mendelian Susceptibility to Mycobacterial Diseases,Journal of Clinical Immunology

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Novel STAT1 Variants in Japanese Patients with Isolated Mendelian Susceptibility to Mycobacterial Diseases
Journal of Clinical Immunology ( IF 7.2 ) Pub Date : 2022-11-07 , DOI: 10.1007/s10875-022-01396-1
Rintaro Ono ₁ , Miyuki Tsumura ₂ , Saho Shima ₃ , Yusuke Matsuda ₄ , Kenji Gotoh ₅ , Yurina Miyata ₁ , Yuko Yoto ₆ , Dan Tomomasa ₇ , Takanori Utsumi ₂ , Hidenori Ohnishi ₈ , Zenichiro Kato _{8,

9} , Naruhiko Ishiwada ₁₀ , Aki Ishikawa ₁₁ , Taizo Wada ₄ , Hisashi Uhara ₁₂ , Ryuta Nishikomori ₃ , Daisuke Hasegawa ₁ , Satoshi Okada ₂ , Hirokazu Kanegane ₁₃

Affiliation

Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan.
Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan.
Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-8641, Japan.
Department of Infection Control and Prevention, Kurume University School of Medicine, Fukuoka, Japan.
Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan.
Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan.
Structural Medicine, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan.
Department of Infectious Diseases, Medical Mycology Research Center, Chiba University, Chiba, Japan.
Department of Medical Genetics, Sapporo Medical University School of Medicine, Sapporo, Japan.
Department of Dermatology, Sapporo Medical University, Sapporo, Japan.
Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8519, Japan.

Purpose

Heterozygous dominant-negative (DN) STAT1 variants 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.

Methods

An 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.

Results

Patient 1.1 was a 20-month-old boy with multifocal osteomyelitis and paravertebral abscesses caused by Mycobacterium bovis bacillus 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) in STAT1, 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 WT STAT1.

Conclusion

Four kindred MSMD subjects with 3 novel variants and 1 known variant in STAT1 were identified in this study. AD STAT1 deficiency might be prevalent in Japanese patients with BCG-associated MSMD.

中文翻译：

对分枝杆菌疾病具有孤立性孟德尔易感性的日本患者中的新 STAT1 变异体

目的

杂合显性失活 (DN) STAT1变异导致常染色体显性 (AD) 孟德尔对分枝杆菌疾病 (MSMD) 的易感性。在本文中，我们描述了日本四个家族的八个 MSMD 病例。

方法

使用从全血样本中提取的基因组 DNA 进行了免疫相关基因组测序的先天性错误。使用桑格测序验证了所识别的变异。通过荧光素酶报告基因测定和 STAT1 缺陷细胞中的共转染测定来评估功能分析。

结果

患者1.1是一名20个月大的男孩，患有由牛分枝杆菌卡介苗（BCG）引起的多灶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，但添加IFN-γ和引流脓肿是有效的。有趣的是，他的母亲（患者 1.2）除了成年后出现治疗反应性结核性脊柱炎外，临床病程平安无事。患者2.1是一名8个月大的男孩，患有卡介苗引起的淋巴结肿大和肺部结节。他对抗分枝杆菌药物反应良好。他的母亲（患者 2.2）身体健康。患者3.1是一名11岁女孩，疑似皮肤结核。她的兄弟（患者 3.2）患有卡介苗病，但他们的母亲（患者 3.3）健康。患者 4 是一名 8 个月大的女孩，患有与卡介苗接种相关的左腋窝和锁骨上淋巴结肿大。家族 1、2 和 3 在STAT1中分别显示出新的杂合变体（V642F、R588C 和 R649G）。 Kindred 4 之前曾报道过杂合变异体 (Q463H)。在 STAT1 缺陷细胞中进行荧光素酶报告基因检测，随后进行 IFN-γ 刺激，证实这些变异体丧失了功能。此外，通过共转染测定，我们证实所有这些变体都对 WT STAT1具有 DN 效应。