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Review
. 2024 Oct 2;25(19):10609.
doi: 10.3390/ijms251910609.

HNF1B Transcription Factor: Key Regulator in Renal Physiology and Pathogenesis

Eloísa Sánchez-Cazorla  1   2 , Noa Carrera  1   2   3 , Miguel Ángel García-González  1   2   3
Affiliations
Review

HNF1B Transcription Factor: Key Regulator in Renal Physiology and Pathogenesis

Eloísa Sánchez-Cazorla et al. Int J Mol Sci. .

Abstract

The HNF1B gene, located on chromosome 17q12, encodes a transcription factor essential for the development of several organs. It regulates the expression of multiple genes in renal, pancreatic, hepatic, neurological, and genitourinary tissues during prenatal and postnatal development, influencing processes such as nephrogenesis, cellular polarity, tight junction formation, cilia development, ion transport in the renal tubule, and renal metabolism. Mutations that alter the function of Hnf1b deregulate those processes, leading to various pathologies characterized by both renal and extrarenal manifestations. The main renal diseases that develop are polycystic kidney disease, hypoplastic or dysplastic kidneys, structural abnormalities, Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), and electrolyte imbalances such as hyperuricemia and hypomagnesemia. Extrarenal manifestations include Maturity-Onset Diabetes of the Young (MODY), hypertransaminasemia, genital and urinary tract malformations, Autism Spectrum Disorder (ASD), and other neurodevelopmental disorders. Patients with HNF1B alterations typically carry either punctual mutations or a monoallelic microdeletion in the 17q12 region. Future research on the molecular mechanisms and genotype-phenotype correlations in HNF1B-related conditions will enhance our understanding, leading to improved clinical management, genetic counseling, monitoring, and patient care.

Keywords: 17q12 region; HNF1B; apico-basal polarity; cilia development; cyst formation; gene expression regulation; intrarenal metabolism; nephrogenesis; renal ion transport; renal physiology.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
(a) Scheme of canonical HNF1B transcript (NM_000458.4) protein domains. aa: amino acid; POUS: Pit-Onc-Unc specific; POUH: Pit-Onc-Unc homeodomain. (b) Phenotypic manifestations associated with HNF1B and their prevalence in the literature. There is a substantial variability in both renal and extrarenal manifestations among HNF1B patients. These patients may exhibit various combinations of these phenotypes. The prevalence of each manifestation shown in the figure has been derived from the article by Vasileiou et al. [20], where they reviewed the prevalence ranges for each condition from 82 published studies on HNF1B patients with clinical data. CAKUT: Congenital Anomalies of the Kidney and Urinary Tract; MODY: Maturity-Onset Diabetes of the Young; ASD: Autism Spectrum Disorder.
Figure 2
Figure 2
Genes regulated by Hnf1b and their associated diseases. Genes involved in nephrogenesis, ion transport, primary cilia, cellular polarity, cellular junctions, and mitochondrial respiration are shown in green, purple, orange, light blue, brown, and dark blue, respectively. Underlined pathologies are renal pathologies [1,2,3,23,34,45,47,48,49]. CAKUT: Congenital Anomalies of the Kidney and Urinary Tract; FSGS: Focal Segmental Glomerulosclerosis; Aa: amino acid.
Figure 3
Figure 3
Nephrogenesis stages and Hnf1b’s role in this process. (a) Kidney details of renal development from embryonic to mature kidneys. (b) Nephron details of renal development from embryonic to mature nephrons. (c) Molecular details and Hnf1b’s role in renal development from embryonic to mature nephrons. UB, Ureteric Bud; MM, Metanephric Mesenchyme.
Figure 4
Figure 4
Ionic transporters regulated by Hnf1b in each tubular segment. Continuous arrows represent transduction processes from gene to protein; dashed arrows represent regulation processes from protein1 to protein2. PT: proximal tubule; TAL: thick ascending limb; DCT: distal convoluted tubule; CD: collecting duct; OAT4: organic anion transporter 4; NPT1: Na+-phosphate transporter 1; URAT1: urate transporter; OAT1: organic anion transporter 1; OAT3: organic anion transporter 3; NKCC2: Na+-K+-Cl- co-transporter 2; Umod: uromodulin; ROMK: renal outer medullary potassium channel; NCC: Na+-Cl- co-transporter; TRPM6: transient receptor potential melastatin type 6; TRPV5: TRP vanilloid type 5; CaSR: calcium-sensing receptor; PTH: parathyroid hormone; FXR: farnesoid X receptor; and AQP2: aquaporin 2.
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