The role of hepatocyte nuclear factor 1β in disease and development

Abstract

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. K E Y W O R D Shepatocyte nuclear factor 1β, HNF1B-associated disease, liver development, MODY, pancreas development, renal cyst and diabetes syndrome

Lineage specific core-regulatory circuits determine gene essentiality in cancer cells

“…These TFs were also part of the hepatocellular carcinoma CRC we predicted for hepatocellular carcinoma from gene essentiality data ( Figure 2B). In addition, our predicted CRC contained additional TFs that have previously been described (El-Khairi and Vallier, 2016;Nguyen et al, 2014) to play important roles during liver development, such as HNF1B (LD-score = 3.79, FDR = 8.66x10 -7 ) or LIN28B (LD-score = 2.29, FDR = 9.06x10 -6 ). As expected, public transcription factor databases (ENCODE Project Consortium, 2004;Lachmann et al, 2010;Matys et al, 2003;Rouillard et al, 2016;Xu et al, 2013) report a large number of TF-target gene relationships (i.e.…”

Influence of IGF2BP2, HMG20A, and HNF1B genetic polymorphisms on the susceptibility to Type 2 diabetes mellitus in Chinese Han population

“…HNF1B gene played the important role in the primary pathophysiology of diabetes. It was involved in the loss of neurogenin-3 (Ngn3)-positive endocrine progenitor cells, pancreatic atrophy, and a reduced insulin sensitivity to endogenous glucose production leading to the reduction of insulin secretion [32]. Previous studies have reported that genetic variations in HNF1B were associated with the susceptibility of T2DM.…”

A novel splice-site mutation of the HNF1B gene in a family with maturity onset diabetes of the young type 5 (MODY5)

“…Early-onset DM cases with renal abnormalities strongly suggest a mutation in the HNF1B gene. Moreover, the pathophysiology of DM in patients with HNF1B mutations is beta-cell dysfunction and reduced insulin secretion as well as reduced insulin sensitivity to endogenous glucose production ( 6 ). The majority of MODY5 patients require early treatment with insulin since they respond poorly to sulphonylureas.…”

“…Mutations predominantly cluster in the first four exons, which encode dimerisation and DNA-binding domains. Most of them can explain a transcriptional impairment of the HNF1B protein ( 6 ). Here, sequencing of coding exons and intron–exon boundaries of the candidate genes allowed us to detect a mutation in an intron.…”