Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1
Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1
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DOI：
10.1210/jc.2003-030046
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发表时间：
2003-09-01
影响因子：
5.8
通讯作者：
Philippe, J
中科院分区：
文献类型：
--
作者：
Schwitzgebel, VM;Mamin, A;Philippe, J
新生儿糖尿病可以是暂时性的，也可以是永久性的。严重形式的永久性新生儿糖尿病可能与胰腺发育不全有关。正常的胰腺发育是由一系列转录因子控制的，其中胰岛素促进因子1(IPF1)起着关键作用。在这里，我们描述了导致胰腺发育不全的两个新的IPF1基因突变。对IPF1基因的外显子1和外显子2进行直接序列分析，发现外显子2的同源盒内有两个点突变。对父母的遗传分析表明，每个突变都来自一个父母。分别位于同源结构域的螺旋1和2的突变显著减少了蛋白质的半衰期，导致细胞内IPF1水平分别为野生型的36%和27%。两种突变形式的IPF1都正常地移位到细胞核，它们对不同已知目标启动子的DNA结合活性与野生型蛋白相似。然而，两个突变的IPF1蛋白，单独或与HNF3β/Foxa2，Pbx1，或异源二聚体E47-Beta2结合时，转录活性降低，这是由于IPF1稳定水平的降低，而不是蛋白质-蛋白质相互作用的减弱。我们的结论是，IPF1水平对人胰腺的形成至关重要。
Neonatal diabetes mellitus can be transient or permanent. The severe form of permanent neonatal diabetes mellitus can be associated with pancreas agenesis. Normal pancreas development is controlled by a cascade of transcription factors, where insulin promoter factor 1 (IPF1) plays a crucial role. Here, we describe two novel mutations in the IPF1 gene leading to pancreas agenesis. Direct sequence analysis of exons 1 and 2 of the IPF1 gene revealed two point mutations within the homeobox in exon 2. Genetic analysis of the parents showed that each mutation was inherited from one parent. Mutations localized in helixes 1 and 2, respectively, of the homeodomain, decreased the protein half-life significantly, leading to intracellular IPF1 levels of 36% and 27% of wild-type levels. Both mutant forms of IPF1 were normally translocated to the nucleus, and their DNA binding activity on different known target promoters was similar to that of the wild-type protein. However, transcriptional activity of both mutant IPF1 proteins, alone or in combination with HNF3beta/Foxa2, Pbx1, or the heterodimer E47-beta2 was reduced, findings accounted for by decreased IPF1 steady state levels and not by impaired protein-protein interactions. We conclude that the IPF1 level is critical for human pancreas formation.