A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant
A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant
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DOI：
10.1007/s10875-019-00631-6
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发表时间：
2019-05-01
影响因子：
9.1
通讯作者：
Feldman, Hagit Baris
中科院分区：
文献类型：
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作者：
Kurolap, Alina;Adiv, Orly Eshach;Feldman, Hagit Baris
目的研究1例男童重症婴幼儿起病结肠炎和嗜酸性胃肠道疾病的临床表型、遗传基础和继发免疫学表型，无复发或严重感染的证据。采用蛋白印迹(WB)和免疫组织化学(IHC)染色进行蛋白表达分析。免疫学检查包括体外T细胞研究、流式细胞仪和细胞周期蛋白分析。结果WES发现了一个与核心家族中的疾病共分离的蛋白调节蛋白和肌球蛋白1连接物2(CARMIL2)基因的纯合子变异：c.1590C>；A；p.Asn530Lys。WB和IHC分析显示，与对照组相比，患者细胞中的蛋白质水平降低。此外，全面的免疫学检查显示，血液携带的调节性T细胞(T-reg)频率严重降低，体外CD4(+)T细胞的增殖和T-reg的生成受到损害。结论CARMIL2致病基因变异与免疫缺陷综合征有关，以反复感染为特征，偶尔伴有慢性腹泻。我们发现CARMIL2免疫缺陷与显著胃肠道疾病患者免疫群体格局的显著改变有关。这一病例提供了证据，证明CARMIL2基因应该是诊断极早发病的炎症性和嗜酸性胃肠道疾病儿童的候选基因，即使没有观察到免疫缺陷的迹象。
Purpose This study aimed to characterize the clinical phenotype, genetic basis, and consequent immunological phenotype of a boy with severe infantile-onset colitis and eosinophilic gastrointestinal disease, and no evidence of recurrent or severe infections.Methods Trio whole-exome sequencing (WES) was utilized for pathogenic variant discovery. Western blot (WB) and immunohistochemical (IHC) staining were used for protein expression analyses. Immunological workup included in vitro T cell studies, flow cytometry, and CyTOF analysis.Results WES revealed a homozygous variant in the capping protein regulator and myosin 1 linker 2 (CARMIL2) gene: c.1590C>A; p.Asn530Lys which co-segregated with the disease in the nuclear family. WB and IHC analyses demonstrated reduced protein levels in patient's cells compared with controls. Moreover, comprehensive immunological workup revealed severely diminished blood-borne regulatory T cell (T-reg) frequency and impaired in vitro CD4(+) T cell proliferation and T-reg generation. CyTOF analysis showed significant shifts in the patient's innate and adaptive immune cells compared with healthy controls and ulcerative colitis patients.Conclusions Pathogenic variants in CARMIL2 have been implicated in an immunodeficiency syndrome characterized by recurrent infections, occasionally with concurrent chronic diarrhea. We show that CARMIL2-immunodeficiency is associated with significant alterations in the landscape of immune populations in a patient with prominent gastrointestinal disease. This case provides evidence that CARMIL2 should be a candidate gene when diagnosing children with very early onset inflammatory and eosinophilic gastrointestinal disorders, even when signs of immunodeficiency are not observed.