Menegatti Elisa, Nardacchione Antonella, Alpa Mirella, Agnes Cecilia, Rossi Daniela, Chiara Marica, Modena Vittorio, Sena Luigi M, Roccatello Dario
Dipartimento di Medicina e Oncologia Sperimentale, Cattedre di Patologia Clinica, Università di Torino, Italy.
Lab Invest. 2002 May;82(5):543-6. doi: 10.1038/labinvest.3780448.
Uteroglobin (UG) is a multifunctional protein with anti-inflammatory/immunomodulatory properties. The UG gene is located on the long arm of chromosome 11 (11q12.3-q13.1) in a region linked to some immune disorders. A guanine-adenine substitution at position 38 (A38G) has been found in the noncoding region of exon 1 that is significantly correlated with an increased risk of developing immune-mediated diseases. Recently an experimental model of UG knockout mice showed that in mice, UG deficiency causes severe glomerulopathy with mesangial deposition of IgA-fibronectin complexes. To detect the presence of polymorphisms in the UG coding sequence, the DNA of 109 patients with IgA nephropathy (IgAN), and 32 patients with systemic lupus erythematosus (SLE) were tested for the nucleotide sequence of all three UG exons by heteroduplex analysis. We detected heterozygous DNA only for exon 1 due to the A38G substitution, as confirmed by sequencing. We tested for A38G polymorphism, by restriction endonuclease digestion (Sau96I), both in SLE patients and in IgAN patients. Twenty patients with either membranous nephropathy (12) or focal and segmental glomerular sclerosis and 120 healthy subjects served as controls. Compared with both healthy controls and non-IgA control patients, the frequency of the 38A allele was significantly higher in SLE patients (38 of 64 alleles versus 89 of 240 alleles, p = 0.002, and versus 7 of 40 alleles, p < 0.001). IgAN patients showed an allelic distribution similar to both control groups. A subgroup of 18 IgAN patients undergoing renal replacement therapy because of end-stage renal disease showed a significant increase in 38A allele frequency (5 of 36 38G alleles versus 31 of 36 38A alleles, p < 0.001). UG is an immunomodulatory agent that is able to (a) inhibit the activity of several phospholipase A2 (PLA2s), (b) interfere with the function of both neutrophils and monocytes, and (c) prevent immune recognition, perhaps by masking surface antigens. This could account for the role this molecule plays in SLE. The A38G polymorphism is located within a region corresponding to the rat minimal promoter that proved to be important in the transcriptional regulation of UG. Although the significance of any alterations in the UG exon 1 noncoding region in humans has yet to be clarified, initial evidence suggests that it may alter the control of immune response and of inflammation.
子宫珠蛋白（UG）是一种具有抗炎/免疫调节特性的多功能蛋白质。UG基因位于11号染色体长臂（11q12.3 - q13.1）上，该区域与一些免疫性疾病相关。在外显子1的非编码区发现了第38位的鸟嘌呤 - 腺嘌呤替换（A38G），这与发生免疫介导疾病的风险增加显著相关。最近，UG基因敲除小鼠的实验模型表明，在小鼠中，UG缺乏会导致严重的肾小球病，并伴有系膜区IgA - 纤连蛋白复合物沉积。为了检测UG编码序列中的多态性，通过异源双链分析对109例IgA肾病（IgAN）患者和32例系统性红斑狼疮（SLE）患者的DNA进行了所有三个UG外显子的核苷酸序列检测。经测序证实，由于A38G替换，我们仅在外显子1中检测到杂合DNA。我们通过限制性内切酶消化（Sau96I）对SLE患者和IgAN患者进行了A38G多态性检测。20例膜性肾病患者（12例）或局灶节段性肾小球硬化患者以及120名健康受试者作为对照。与健康对照和非IgA对照患者相比，SLE患者中38A等位基因的频率显著更高（64个等位基因中的38个，而240个等位基因中的89个，p = 0.002；与40个等位基因中的7个相比，p < 0.001）。IgAN患者的等位基因分布与两个对照组相似。18例因终末期肾病接受肾脏替代治疗的IgAN患者亚组中，38A等位基因频率显著增加（36个38G等位基因中的5个，而36个38A等位基因中的31个，p < 0.001）。UG是一种免疫调节剂，能够（a）抑制几种磷脂酶A2（PLA2s）的活性，（b）干扰中性粒细胞和单核细胞的功能，以及（c）可能通过掩盖表面抗原阻止免疫识别。这可以解释该分子在SLE中所起的作用。A38G多态性位于与大鼠最小启动子相对应的区域内，该区域在UG的转录调控中被证明是重要的。尽管人类UG外显子1非编码区任何改变的意义尚未阐明，但初步证据表明它可能会改变免疫反应和炎症的控制。
