In vitro and pathological investigations of MODY5 with the R276X-HNF1β (TCF2) mutation
In vitro and pathological investigations of MODY5 with the R276X-HNF1β (TCF2) mutation
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DOI：
10.1507/endocrj.k07-051
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发表时间：
2007-10-01
影响因子：
2
通讯作者：
Tajima, Naoko
中科院分区：
文献类型：
--
作者：
Fujimoto, Kei;Sasaki, Takashi;Tajima, Naoko
青年5型成熟型糖尿病(MODY5)是由肝细胞核因子I P(HNF1β)(TCF2)基因突变引起的，导致包括糖尿病和肾脏异常在内的多种表型，但其临床发病机制尚不清楚。我们描述一位27岁的日本男性，其MODY表型包括肾脏萎缩和多发性肾囊肿。遗传分析显示，患者是HNF1β基因276密码子的无义突变杂合子(CGA或精氨酸为TGA或停止密码子；R276X)。为了阐明这种突变的病理生理学相关性，我们在体外进行了一项研究，在将HNF1β突变基因和胰岛素原基因同时导入小鼠P细胞系MIN6后，对人C肽的分泌进行了监测。对转化的MIN6细胞的功能研究表明，R276X的表达导致葡萄糖刺激的胰岛素分泌显著减少，但对KCI刺激的胰岛素分泌或基础胰岛素分泌没有影响。这些结果表明，R276X在P细胞胰岛素分泌的代谢反应中起负性作用。肾活检标本的光镜和电子显微镜分析表明，囊肿的起源可能是肾小球，但原发病变可能是肾小管。
Maturity-onset diabetes of the young type 5 (MODY5) is caused by mutation of hepatocyte nuclear factor I P (HNF1 beta) (TCF2) gene, resulting in a wide range of phenotypes including diabetes and renal abnormalities, but little is known about the pathogenesis of the clinical spectrum. We describe a 27-year-old Japanese male with the MODY phenotype including an atrophic kidney and multiple renal cysts. Genetic analysis revealed the patient to be heterozygous for a nonsense mutation in codon 276 of the HNF1 beta gene (CGA or Arginine to TGA or stop codon; R276X). To clarify the pathophysiological relevance of this mutation, we conducted an in vitro study monitoring human C-peptide secretion after transfecting both the HNF1 beta mutant cDNA and preproinsulin cDNA into a murine P cell line, MIN6. Functional studies of the transformed MIN6 cells indicated that expression of the R276X caused a significant decrease in glucose-stimulated insulin secretion but no change in either KCI-stimulated or basal insulin secretion. These results suggest that the R276X functions in a negative manner in regard to metabolic responses of insulin secretion in P cells. Analysis with light and electron microscopy on biopsied kidney specimens suggested that the origin of the cysts might be glomeruli but the primary lesion could be tubules.