Gragnoli Claudia, Stanojevic Violeta, Gorini Antonio, Von Preussenthal Guido Menzinger, Thomas Melissa K, Habener Joel F
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Boston, MA 02114, USA.
Metabolism. 2005 Aug;54(8):983-8. doi: 10.1016/j.metabol.2005.01.037.
Maturity-onset diabetes of the young (MODY) is a monogenic autosomal-dominant form of diabetes mellitus with onset before 25 years of age. Genetic variation in insulin promoter factor-1 (IPF1) (MODY4) is uncommon but may contribute to early- or late-onset diabetes as part of a polygenic background. IPF1 is a homeodomain transcription factor required for pancreas development. Our aim was to identify whether IPF1 gene mutations play a role in Italian early-onset type 2 diabetic (T2D) patients and what functional impact mutations may have in the beta cell. We screened 40 Italian early-onset type 2 diabetic probands for IPF1 mutations, performed oral glucose tolerance tests in the unaffected family members, and performed in vitro functional studies of the mutant variant. In an extended family (Italy-6) of 46 members with clinical phenotypes of gestational diabetes, MODY, and T2D, a single nucleotide change of CCT to ACT was identified at codon 33 resulting in a Pro to Thr substitution (P33T) in the IPF1 transactivation domain that also contributes to an altered metabolic status in the unaffected NM subjects. Of the 22 genotyped Italy-6 members, 9 carried the P33T allele (NM), of whom 5 have either T2D or elevated fasting glucose levels. Oral glucose tolerance tests showed higher glucose levels at 90 minutes in unaffected NM compared with unaffected NN subjects. Of the 5 female pregnant carriers of the IPF1 mutation, 4 had pregnancies complicated by reduced birth weights, miscarriages, or early postnatal deaths. In studies in vitro, the IPF1 mutant protein (P33T) showed a reduction in DNA-binding and transcriptional activation functions as compared to the wild-type IPF1 protein. Our findings suggest that the P33T IPF1 mutation may provide an increased susceptibility to the development of gestational diabetes and MODY4 in the Italy-6 pedigree.
青年发病的成年型糖尿病（MODY）是一种单基因常染色体显性形式的糖尿病，发病年龄在25岁之前。胰岛素启动因子-1（IPF1）（MODY4）的基因变异并不常见，但作为多基因背景的一部分，可能导致早发或晚发糖尿病。IPF1是胰腺发育所需的一种同源域转录因子。我们的目的是确定IPF1基因突变在意大利早发2型糖尿病（T2D）患者中是否起作用，以及这些突变对β细胞可能有什么功能影响。我们对40名意大利早发2型糖尿病先证者进行了IPF1突变筛查，对未受影响的家庭成员进行了口服葡萄糖耐量试验，并对突变体进行了体外功能研究。在一个有46名成员的大家庭（意大利-6）中，其临床表型包括妊娠期糖尿病、MODY和T2D，在密码子33处发现了一个从CCT到ACT的单核苷酸变化，导致IPF1反式激活域中的脯氨酸被苏氨酸取代（P33T），这也导致了未受影响的NM个体代谢状态的改变。在22名进行基因分型的意大利-6成员中，9人携带P33T等位基因（NM），其中5人患有T2D或空腹血糖水平升高。口服葡萄糖耐量试验显示，与未受影响的NN个体相比，未受影响的NM个体在90分钟时的血糖水平更高。在5名携带IPF1突变的女性孕妇中，4人的妊娠出现了出生体重降低、流产或产后早期死亡等并发症。在体外研究中，与野生型IPF1蛋白相比，IPF1突变蛋白（P33T）的DNA结合和转录激活功能降低。我们的研究结果表明，P33T IPF1突变可能使意大利-6家系中妊娠期糖尿病和MODY4的发病易感性增加。
