Maturity-onset diabetes of the young 1 (MODY1) is a monogenic diabetes condition caused by heterozygous HNF4A mutations. We investigate how HNF4A haploinsufficiency from a MODY1/HNF4A mutation influences the development of foregut-derived liver and pancreatic cells through differentiation of human induced pluripotent stem cells from a MODY1 family down the foregut lineage. In MODY1-derived hepatopancreatic progenitors, which expressed reduced HNF4A levels and mislocalized HNF4A, foregut genes were downregulated, whereas hindgut-specifying HOX genes were upregulated. MODY1-derived hepatocyte-like cells were found to exhibit altered morphology. Hepatic and β cell gene signatures were also perturbed in MODY1-derived hepatocyte-like and β-like cells, respectively. As mutant HNF4A (p.Ile271fs) did not undergo complete nonsense-mediated decay or exert dominant negativity, HNF4A-mediated loss of function is likely due to impaired transcriptional activation of target genes. Our results suggest that in MODY1, liver and pancreas development is perturbed early on, contributing to altered hepatic proteins and β cell defects in patients.

年轻的成熟期糖尿病 1 (MODY1) 是由杂合HNF4A突变引起的单基因糖尿病。我们研究了来自 MODY1/HNF4A 突变的 HNF4A 单倍体不足如何通过来自 MODY1 家族的人类诱导多能干细胞向前肠谱系分化来影响前肠源性肝脏和胰腺细胞的发育。在 MODY1 衍生的肝胰腺祖细胞中，表达降低的 HNF4A 水平和错误定位的 HNF4A，前肠基因被下调，而后肠特异性HOX基因被上调。发现 MODY1 衍生的肝细胞样细胞表现出改变的形态。肝脏和β细胞基因特征也分别在MODY1衍生的肝细胞样和β样细胞中受到干扰。由于突变体 HNF4A (p.Ile271fs) 没有经历完全无义介导的衰变或发挥显性负性，因此 HNF4A 介导的功能丧失可能是由于靶基因的转录激活受损。我们的研究结果表明，在 MODY1 中，肝脏和胰腺的发育早期受到干扰，导致患者的肝蛋白改变和 β 细胞缺陷。