The diabetic phenotype in HNF4A mutation carriers is moderated by the expression of HNF4A isoforms from the P1 promoter during fetal development
The diabetic phenotype in HNF4A mutation carriers is moderated by the expression of HNF4A isoforms from the P1 promoter during fetal development
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DOI：
10.2337/db07-1742
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发表时间：
2008-06-01
期刊：
影响因子：
7.7
通讯作者：
Hattersley, Andrew T.
中科院分区：
文献类型：
--
作者：
Harries, Lorna W.;Locke, Jonathan M.;Hattersley, Andrew T.
选择性剪接HNF 4A基因突变导致年轻人成熟型糖尿病（MODY）。我们表征了人类组织中HNF 4A转录本的空间和发育表达模式，并研究了它们作为MODY表型潜在调节剂的作用。研究设计和方法-我们通过亚型特异性实时PCR测量了人类成人组织和妊娠期胎儿胰腺中HNF 4A亚型的表达。在190例HNF 4A突变患者队列中评估突变位置与诊断年龄或年龄相关的突变率之间的相关性。HNF 4A在成人胰腺中仅由P2启动子表达，但从受孕后9周直到至少26周，胎儿胰腺中高达23%的表达是P1起源的。在任何组织中均未检测到HNF 4A 4 -6转录物。在整个胰腺中，HNF 4A 9的表达高于从内分泌胰腺分离的胰岛中的表达（相对水平22 vs. 7%）。外显子9和10突变的患者（HNF 4A 3、HNF 4A 6和HNF 4A 9亚型缺失）比外显子2-8突变的患者（所有亚型均受影响）更晚发生糖尿病（40 vs. 24岁; P = 0.029）。外显子9/10的突变也与年龄相关的突变率降低有关。（55岁时，53%对10%无糖尿病;结论-我们得出结论，HNF 4A P1启动子衍生的同种型在人胎儿胰腺中表达，但在成人胰腺中不表达，并且它们在胰腺发育过程中的存在可能会缓解HNF 4A基因突变个体的糖尿病表型。
OBJECTIVE-Mutations in the alternatively spliced HNF4A gene cause maturity-onset diabetes of the young (MODY). We characterized the spatial and developmental expression patterns of HNF4A transcripts in human tissues and investigated their role as potential moderators of the MODY phenotype.RESEARCH DESIGN AND METHODS-We measured the expression of HNF4A isoforms in human adult tissues and gestationally staged fetal pancreas by isoform-specific real-time PCR. The correlation between mutation position and age of diagnosis or age-related penetrance was assessed in a cohort of 190 patients with HNF4A mutations.RESULTS-HNF4A was expressed exclusively from the P2 promoter in adult pancreas, but from 9 weeks until at least 26 weeks after conception, up to 23% of expression in fetal pancreas was of P1 origin. HNF4A4-6 transcripts were not detected in any tissue. In whole pancreas, HNF4A9 expression was greater than in islets isolated from the endocrine pancreas (relative level 22 vs. 7%). Patients with mutations in exons 9 and 10 (absent from HNF4A3, HNF4A6, and HNF4A9 isoforms) developed diabetes later than those with mutations in exons 2-8, where all isoforms were affected (40 vs. 24 years; P = 0.029). Exon 9/10 mutations were also associated with a reduced age-related penetrance (53 vs. 10% without diabetes at age 55 years; P < 0.00001).CONCLUSIONS-We conclude that isoforms derived from the HNF4A P1 promoter are expressed in human fetal, but not adult, pancreas, and that their presence during pancreatic development may moderate the diabetic phenotype in individuals with mutations in the HNF4A gene.