Liang Jianying, Huang Peichen, Li Huaguo, Zhang Jia, Ni Cheng, Wang Yirong, Shen Jinwen, Li Chunxiao, Kang Lu, Chen Jie, Zhang Hui, Wang Zhen, Zhang Zhen, Li Ming, Yao Zhirong
Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
Department of Stomatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Hum Genet. 2017 Feb;136(2):241-252. doi: 10.1007/s00439-016-1750-y. Epub 2016 Nov 29.
Geographic tongue (GT) is a benign inflammatory disorder of unknown etiology. Epidemiology and histopathology in previous studies found that generalized pustular psoriasis (GPP) is a factor associated with GT, but the molecular mechanism remains obscure. To investigate the mechanism of GT, with and without GPP, three cohorts were recruited to conduct genotyping of IL36RN, which is the causative gene of GPP. In a family spanning three generations and diagnosed with only GT ("GT alone"), GT was caused by the c.115+6T>C/p.Arg10ArgfsX1 mutation in the IL36RN gene. An autosomal dominant inheritance pattern with incomplete penetrance was observed. In the cohort consisting of sporadic cases of "GT alone" (n = 48), significant associations between GT and three IL36RN variants (c.115+6T>C/p.Arg10ArgfsX1, c.169G>A/p.Val57Ile and c.29G>A/p.Arg10Gln) were shown. In the GPP patient cohort (n = 56) and GPP family member cohort (n = 67), a significant association between the c.115+6T>C mutation and the simultaneous presence of GPP and GT was observed when compared to the presence of GPP without GT (P < 0.05). Biopsies revealed similarities among GT patients with different genotypes (AA, Aa and aa), with the neutrophils prominently infiltrating the epidermis. Western-blot analysis showed that the expression ratio of IL-36Ra/IL-36γ in lesioned tongues with individuals harboring different genotypes (AA, Aa and aa, n = 3, respectively) decreased significantly compared to controls (n = 3). We describe the mechanism of GT for the first time: some cases of GT are caused by IL36RN mutations, while those lacking mutations are associated with an imbalance in expression between IL-36Ra and IL-36γ proteins in tongue tissue.
地图舌（GT）是一种病因不明的良性炎症性疾病。既往研究中的流行病学和组织病理学发现，泛发性脓疱型银屑病（GPP）是与地图舌相关的一个因素，但其分子机制仍不清楚。为了研究有或无GPP的地图舌的发病机制，招募了三个队列对IL36RN进行基因分型，IL36RN是GPP的致病基因。在一个三代家族中，仅诊断为地图舌（“单纯地图舌”），地图舌是由IL36RN基因中的c.115+6T>C/p.Arg10ArgfsX1突变引起的。观察到一种具有不完全外显率的常染色体显性遗传模式。在由“单纯地图舌”散发病例组成的队列（n = 48）中，显示地图舌与三个IL36RN变异体（c.115+6T>C/p.Arg10ArgfsX1、c.169G>A/p.Val57Ile和c.29G>A/p.Arg10Gln）之间存在显著关联。在GPP患者队列（n = 56）和GPP家庭成员队列（n = 67）中，与无地图舌的GPP患者相比，观察到c.115+6T>C突变与GPP和地图舌同时存在之间存在显著关联（P < 0.05）。活检显示不同基因型（AA、Aa和aa）的地图舌患者之间存在相似性，中性粒细胞显著浸润表皮。蛋白质印迹分析表明，与对照组（n = 3）相比，具有不同基因型（AA、Aa和aa，每组n = 3）的患者病变舌中IL-36Ra/IL-36γ的表达比率显著降低。我们首次描述了地图舌的发病机制：部分地图舌病例由IL36RN突变引起，而无突变的病例与舌组织中IL-36Ra和IL-36γ蛋白表达失衡有关。
