HNF1B is a member of the HNF class of the homeobox genes and encodes the tissue restricted transcription factor HNF1B (TCF2, vHNF1, LFB3). Its DNA binding domain is characterized by a POU-specific (POU_S) domain and an atypical homodomain, referred to as POU-homeo (POU_H) domain (Figure 1)^[1][2][3][4]. This structure is also observed in the related HNF1A gene. Both genes are highly conserved in structure and function within vertebrates (from zebrafish to human). A unique feature of HNF1B is a 26 amino acid sequence deleted in the splice variant B. This segment is also found in Xenopus and participates in the nephrogenic function of HNF1B (Figure 1)^[5].

Mutations in humans cause multi-system disease with renal defects, diabetes and genitourinary tract abnormalities as the most prominent features ^{[2][4][6] [7]}. These defects can largely be verified in animal models and several genes have been identified as essential targets that are not properly functioning in patients with mutated HNF1B (Figure 2). Since deletion of the entire HNF1B gene is frequently found in human patients, it seems likely that dysfunction reflects a gene dosage effect ^[8]. However, some mutated factors behave as dominant negative proteins that may possibly inactivate the wild-type protein derived from the normal allele ^[9][10]. Expression of distinct mutation of human HNF1B in Xenopus embryos displays differential morphogenetic potential in kidney formation ^[9], but it is unclear whether these differences contribute to phenotypic variation seen in human patients.

Functional assays in the mouse have identified three regulatory sites in the HNF1B gene locus involved in bile duct formation, mesenchymal-epithelial transition (MET) and neural tube expression (Figure 3).

HNF1B is expressed in early embryogenesis and embryos with homozygous HNF1B deletion die due to defective visceral endoderm differentiation ^[11][12]. However, mice with a heterozygous mutation are healthy and thus do not mirror the situation in humans. At later stages HNF1B is expressed in epithelia of the liver, lung, pancreas, digestive tract and kidney, but also in the developing hindbrain. More details on the deletion and overexpression of HNF1B in the mouse can be found in Fig. 3 in the mouse HNF1B article (http://www.cisreg.ca/cgi-bin/tfe/articles.pl?tfid=867).