Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge, UK.
Wellcome Trust Sanger Institute, Cambridge, UK.
Diabetes Obes Metab. 2016 Sep;18 Suppl 1:23-32. doi: 10.1111/dom.12715.
Heterozygous mutations in the gene that encodes the transcription factor hepatocyte nuclear factor 1β (HNF1B) result in a multi-system disorder. HNF1B was initially discovered as a monogenic diabetes gene; however, renal cysts are the most frequently detected feature. Other clinical features include pancreatic hypoplasia and exocrine insufficiency, genital tract malformations, abnormal liver function, cholestasis and early-onset gout. Heterozygous mutations and complete gene deletions in HNF1B each account for approximately 50% of all cases of HNF1B-associated disease and may show autosomal dominant inheritance or arise spontaneously. There is no clear genotype-phenotype correlation indicating that haploinsufficiency is the main disease mechanism. Data from animal models suggest that HNF1B is essential for several stages of pancreas and liver development. However, mice with heterozygous mutations in HNF1B show no phenotype in contrast to the phenotype seen in humans. This suggests that mouse models do not fully replicate the features of human disease and complementary studies in human systems are necessary to determine the molecular mechanisms underlying HNF1B-associated disease. This review discusses the role of HNF1B in human and murine pancreas and liver development, summarizes the disease phenotypes and identifies areas for future investigations in HNF1B-associated diabetes and liver disease.
编码转录因子肝细胞核因子 1β（HNF1B）的基因突变导致多系统疾病。HNF1B 最初被发现是一种单基因糖尿病基因；然而，肾囊肿是最常发现的特征。其他临床特征包括胰腺发育不良和外分泌功能不全、生殖道畸形、肝功能异常、胆汁淤积和早发性痛风。HNF1B 中的杂合突变和完全基因缺失各占 HNF1B 相关疾病所有病例的约 50%，可能表现为常染色体显性遗传或自发发生。没有明确的基因型-表型相关性表明，单倍不足是主要的疾病机制。来自动物模型的数据表明，HNF1B 对于胰腺和肝脏发育的几个阶段都是必不可少的。然而，与人类所见的表型相比，HNF1B 杂合突变的小鼠没有表现出表型。这表明小鼠模型不能完全复制人类疾病的特征，需要在人类系统中进行补充研究，以确定 HNF1B 相关疾病的分子机制。这篇综述讨论了 HNF1B 在人类和鼠类胰腺和肝脏发育中的作用，总结了疾病表型，并确定了 HNF1B 相关糖尿病和肝病未来研究的领域。
