伴G6PD基因变异狼疮性肾炎患者的临床特点及基因变异分析  

Clinicopathological and genetic features of lupus nephritis patients with G6PD variants

作　　者：金英 罗晓鑫 梁丹丹 彭嘉惠 张洋洋 涂远茂 刘志红 张昌明 JIN Ying;LUO Xiaoxin;LIANG Dandan;PENG Jiahui;ZHANG Yangyang;TU Yuanmao;LIU Zhihong;ZHANG Changming(National Clinical Research Center of Kidney Diseases,Jinling Hospital,Nanjing Medical University,Nanjing 210016,China;Zhejiang University School of Medicine,Hangzhou 310058,China)

机构地区：[1]南京医科大学金陵临床医学院(东部战区总医院)、国家肾脏疾病临床医学研究中心、全军肾脏病研究所,南京210016 [2]浙江大学医学院

出　　处：《肾脏病与透析肾移植杂志》2023年第3期207-213,共7页Chinese Journal of Nephrology,Dialysis & Transplantation

基　　金：国家自然科学基金(82170739);江苏省科技资源统筹服务平台肾脏疾病样本库运行经费(BM2015004-1);江苏省重大疾病生物资源样本库开放课题(JSRB2021-02)。

摘　　要：目的:分析3例携带葡萄糖6磷酸脱氢酶(G6PD)基因变异的狼疮性肾炎(LN)患者的临床及病理特点,讨论G6PD基因变异检测在系统性红斑狼疮(SLE)中的临床价值。方法:收集3例患者的临床病理资料。采用全外显子测序检测LN患者的G6PD基因变异,Sanger测序检测亲属G6PD基因变异情况。G6PD/6磷酸葡萄糖脱氢酶(6PGD)比值法测定G6PD酶活性。定量聚合酶链反应(qPCR)和细胞因子微球检测技术(CBA)检测其中2例患者的炎症状态特征。结果:3例患者均曾有血三系减低,Coombs试验均阴性,红细胞碎片均阳性,G6PD酶活性均缺乏。2例男性患者为G6PD c.G1466T(p.R489L)半合子变异,均遗传自母亲;1例女性患者为G6PD c.G1466T(p.R489L)及c.G1478A(p.R493H)复合杂合变异,分别遗传自父母双方。qPCR及CBA检测发现,与正常对照相比,2例患者血细胞干扰素刺激基因IFIT1、IFI44L、OAS1与MX2表达明显升高,血清白细胞介素8(IL-8)及γ干扰素诱导蛋白10(IP-10)明显升高,提示Ⅰ型干扰素信号通路的过度激活及炎性细胞因子的过度产生。结论:合并G6PD基因变异的LN患者常以贫血为首发或突出临床表现,伴Ⅰ型干扰素信号通路的过度激活以及炎性细胞因子的过度产生,其在SLE发病中的作用值得进一步研究。Objective:To summarize the clinical and pathological characteristics of 3 patients with lupus nephritis who carried the missense variants of glucose 6-phosphate dehydrogenase(G6PD)and to discuss the clinical value of G6PD variants detection in systemic lupus erythematosus.Methodology:We collected the clinical and pathological data of 3 patients with lupus nephritis in Jinling Hospital.Pathogenic variants was screened by whole-exome sequencing(WES)in the patients and validated by Sanger sequencing in family members.G6PD/6PGD ratio method was used to test the G6PD enzyme activity.Quantitative polymerase chain reaction(qPCR)and cytometric bead array(CBA)was used to detect inflammatory signatures in two patients.Results:All the 3 patients had a history of pancytopenia.Coombs tests were negative,but the red blood cell fragments were all positive.WES identified two kinds of variants in G6PD gene.Two males had a hemizygous variant of c.G1466T(p.R489L)inherited from their mother,while the female patient had a compound heterozygous variant of c.G1466T(p.R489L)and c.G1478A(p.R493H)inherited from the parents.The G6PD enzyme activity were all deficient.We further identified hyperactivation signatures of type I interferon signaling and overproduction of pro-inflammatory cytokines in the blood of two patients.Compared with the normal controls,the expression of in terferon-stimulated genes IFIT1,IFI44L,OAS1 and MX2 in blood cells of two patients was significantly higher,as well as the serum IL-8 and IP-10 levels.Conclusion:Lupus nephritis patients with G6PD gene variants may present with anemia as the first or prominent clinical manifestation,accompanied by excessive activation of type I interferon signal pathway and excessive production of inflammatory cytokines in the blood.Its role in the pathogenesis of SLE deserves further study.

关 键 词：葡萄糖6磷酸脱氢酶 系统性红斑狼疮 狼疮性肾炎 溶血性贫血 

分 类 号：R593.242[医药卫生—内科学]