CBLB
基因和小兒自體免疫性甲狀腺疾病 - 病例對照性研究 Graves 氏病和橋本氏甲狀腺炎是多基因複合性疾病（ multi-genes complex diseases ）。病人之手足 和子女的發病率（ risks ）比一般民眾高。同卵雙胞間的符合率（ concordance rate ）比異卵雙胞間 高。這些現象表示基因在此類疾病中扮演著重要的角色。自體免疫性抗體以及胰島或甲狀腺內 B 和 T 細胞的浸潤顯示這些疾病為自體免疫機轉所致。 Komeda diabetes-prone (KDP) 鼠是一種人類 第１型糖尿病之自發性動物模型（ animal model ） , 其特徵為胰島細胞之自體免疫性破壞 , 兩性間 無差異之迅速發病成明顯糖尿病 , 與無顯著 T 細胞缺乏症（ T-cell lymphopenia ）。病理檢查也可 見包括甲狀腺之多腺體侵犯（ polyglandular involvement ）。取自 KDP 鼠之 cblb cDNA 定序後 發現一 C→T 純合子突變（ homozygous nonsense mutation ）（ Arg455X ）。這個突變使得 cblb 蛋白短少了 484 個胺基酸 , 包括 proline-rich region 和 leucine zipper domain 。顯然 cblb 突變是 造成 KDP 鼠罹患第１型糖尿病之主因。 CBLB 基因決定一個大蛋白 , 分別具有 proline rich doma in,nuclear localization signal,C3HC4 zinc finger 和 putative leucine zipper 。 cblb 蛋白會與訊號傳遞 蛋白（ signal transduction proteins ）交互作用而來調節其功能或受其調控。 Cblb 是自體免疫機轉 之負向調控者。 Cblb 信息傳遞路徑之缺損會導致人類自體免疫性疾病 , 包括第１型糖尿病 ; 葛瑞夫 茲氏病 ; 橋本氏甲狀腺炎。所以 cblb 基因是研究自體免疫機轉之候選基因（ candidate gene ）。 C BLB gene 上有七個單一核 ? 酸多形性（ SNP ） , 本研究根據目前可得的資料庫（包括 NCBI 所建 立的） , 找出對偶基因頻率大於 0.20 的四個 SNP, 經基因定序証實其中 2 個 SNP 存在於國人的這個 基因上。之後利用 PCR 產物 ;RFLP 的切割位置 , 去分析 60 位橋本氏甲狀腺炎病人及 338 位正常的 對照組的 cblb gene 的多形性和突變 , 同時藉由 Chi-square test; Hardy-Weinberg equilibrium 檢測 cblb gene 和疾病的相關性 (association) 。結果顯示此兩 SNPs (rs2305035 與 rs2305037) 與橋本氏甲狀腺 炎無顯著相關。本實驗無法證實 cblb gene 和甲狀腺炎具有顯著的相關性 , 因此在我們國人裡 ,CBLB 可能不是橋本氏甲狀腺炎的重要易罹病基因。
The CBLB gene and autoimmune thyroid disease in children-Case- control study
Graves' disease, and Hashimoto's thyroiditis are multi-genes complex diseases. The risks of the diseases to siblin gs and offspring of affected individuals are higher than to general population. The concordance rate between monozygotic twi ns is greater than that between dizygotic twins. These suggest that genes play some role in the diseases. The presence of autoa ntibodies and infiltration of both B and T cells in either islets or thyroid indicate autoimmunity. The Komeda diabetes-prone (KDP) rat is a spontaneous animal model of human type 1 diabetes and characterized by autoimmune destruction of pancreati c -cells, rapid onset of overt diabetes with no sex difference, and no significant T-cell lymphopenia. Pathological findings als o show polyglandular involvement including thyroid gland. Sequence analysis of the cblb cDNA from the KDP rat identified a C→T homozygous nonsense mutation (arginine to a stop at codon 455, Arg455X) that removes 484 amino acids, including t he proline-rich region and leucine zipper domain. Thus cblb contributes significantly to the development of type 1 diabetes in the KDP rat. The cblb gene encodes a large protein that has a proline rich domain, a nuclear localization signal, a C3HC4 zinc finger, and a putative leucine zipper. The cblb protein can interact with signal transduction proteins to regulate their function o r to be regulated by them. Cblb functions as a negative regulator of autoimmunity. Impairment of the cblb signaling pathway may contribute to human autoimmune diseases. Thus, the gene cblb is a potential candidate for autoimmunity. The defection of Cblb signal transduction pathway will lead to autoimmune disease including Diabetes mellitus type I, Grave’s disease and Hashimoto disease. As a result the CBLB gene is one of the candidate gene in the research of autoimmune mechanism.
