T130I mutation in HNF-4α gene is a loss-of-function mutation in hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects
T130I mutation in HNF-4α gene is a loss-of-function mutation in hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects
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DOI：
10.1007/s00125-003-1067-y
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发表时间：
2003-03
期刊：
影响因子：
8.2
通讯作者：
Q. Zhu;K. Yamagata;Atsuko Miura;N. Shihara;Yukio Horikawa;J. Takeda;J. Miyagawa;Y. Matsuzawa
中科院分区：
文献类型：
--
作者：
Q. Zhu;K. Yamagata;Atsuko Miura;N. Shihara;Yukio Horikawa;J. Takeda;J. Miyagawa;Y. Matsuzawa
目的/假设肝细胞核因子 (HNF)-4α 基因突变导致一种青少年发病型糖尿病 (MODY1)。 T130I 突变是一种罕见的错义突变，它影响 DNA 结合域中的保守氨基酸。这种突变可以在一般人群中发现，因此这种变异本身不会引起MODY。然而，其在迟发性 2 型糖尿病发展中的重要性尚不清楚。方法我们对 423 名无亲属关系的日本迟发性 2 型糖尿病患者和 354 名无亲属关系的非糖尿病对照受试者进行了 HNF-4α 基因 T130I 突变的筛查。使用报告基因测定评估T130I-HNF-4α的反式激活能力。结果2型糖尿病患者中T130I突变的频率高于对照受试者（p=0.015，比值比4.3，95%CI 1.24-14.98）。与无此突变的患者相比，有 T130I 突变的 2 型糖尿病患者的血清 HDL 胆固醇浓度较低 (p=0.006)。报告基因分析表明，与野生型HNF-4α相比，Hela和MIN6细胞中T130I-HNF-4α转录活性并未受损，但在HepG2和原代培养的小鼠肝细胞中转录活性降低（野生型的27-78%，p<0.05）。结论/解释我们的研究结果表明，T130I-HNF-4α是肝细胞中的功能丧失突变，并且该突变与日本受试者患有晚发 2 型糖尿病。 HNF-4α基因中的T130I突变可能与日本人群2型糖尿病的发生有关。
Aims/hypothesisMutations in hepatocyte nuclear factor(HNF)-4αgene cause a form of maturity-onset diabetes of the young (MODY1). The T130I mutation is a rare missense mutation, which affects a conserved amino acid in a DNA binding domain. This mutation can be found in the general population, so this variant alone does not cause MODY. However, its significance in the development of late-onset Type 2 diabetes is not known.MethodsWe screened 423 unrelated Japanese patients with late-onset Type 2 diabetes and 354 unrelated non-diabetic control subjects for the T130I mutation in theHNF-4αgene. The transactivation ability of T130I-HNF-4α was assessed using reporter gene assay.ResultsThe frequency of the T130I mutation was higher in Type 2 diabetic patients (p=0.015, odds ratio 4.3, 95%CI 1.24–14.98) than control subjects. The serum HDL-cholesterol concentration was lower in Type 2 diabetic patients with the T130I mutation compared with those without this mutation (p=0.006). Reporter gene analysis showed that T130I-HNF-4α transcriptional activity was not impaired compared with wild-type HNF-4α in Hela and MIN6 cells, but it was reduced in HepG2 and primary cultured mouse hepatocytes (27–78% of wild type,p<0.05).Conclusion/interpretationOur findings suggest that T130I-HNF-4α is a loss-of-function mutation in hepatocytes and that this mutation is associated with late-onset Type 2 diabetes in Japanese subjects. The T130I mutation in theHNF-4αgene might be involved in the development of Type 2 diabetes in the Japanese population.