Harries Lorna W, Locke Jonathan M, Shields Beverley, Hanley Neil A, Hanley Karen Piper, Steele Anna, Njølstad Pål R, Ellard Sian, Hattersley Andrew T
Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, UK.
Diabetes. 2008 Jun;57(6):1745-52. doi: 10.2337/db07-1742. Epub 2008 Mar 20.
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.
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.
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).
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.
选择性剪接的肝细胞核因子4A（HNF4A）基因突变可导致青年发病的成年型糖尿病（MODY）。我们对HNF4A转录本在人体组织中的空间和发育表达模式进行了表征，并研究了它们作为MODY表型潜在调节因子的作用。
我们通过亚型特异性实时定量PCR检测了HNF4A亚型在成人组织和不同妊娠阶段的胎儿胰腺中的表达。在190例HNF4A基因突变患者队列中评估突变位置与诊断年龄或年龄相关外显率之间的相关性。
HNF4A在成人胰腺中仅从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%的表达源自P1。在任何组织中均未检测到HNF4A4-6转录本。在整个胰腺中，HNF4A9的表达高于从内分泌胰腺分离的胰岛（相对水平分别为22%和7%）。外显子9和10发生突变的患者（HNF4A3、HNF4A6和HNF4A9亚型中不存在这些突变）患糖尿病的时间晚于外显子2-8发生突变的患者（所有亚型均受影响）（40岁对24岁；P = 0.029）。外显子9/10突变还与年龄相关外显率降低有关（55岁时无糖尿病的比例分别为53%和10%；P < 0.00001）。
我们得出结论，源自HNF4A P1启动子的亚型在人类胎儿胰腺而非成人胰腺中表达，并且它们在胰腺发育过程中的存在可能会减轻HNF4A基因突变个体的糖尿病表型。
