HNF1B-associated clinical phenotypes: the kidney and beyond

Abstract

Mutations in HNF1B, the gene encoding hepatocyte nuclear factor 1β are the most commonly identified genetic cause of renal malformations. HNF1B was first identified as a disease gene for diabetes (MODY5) in 1997, and its involvement in renal disease was subsequently noted through clinical observations in pedigrees affected by MODY5. Since then, a whole spectrum of associated phenotypes have been reported, including genital malformations, autism, epilepsy, gout, hypomagnesaemia, primary hyperparathyroidism, liver and intestinal abnormalities and a rare form of kidney cancer. The most commonly identified mutation, in approximately 50 % of patients, is an entire gene deletion occurring in the context of a 17q12 chromosomal microdeletion that also includes several other genes. Some of the associated phenotypes, especially the neurologic ones, appear to occur only in the context of this microdeletion and thus may not be directly linked to HNF1B. Here we review the spectrum of associated phenotypes and discuss potential implications for clinical management.

Genetic causes of hypomagnesemia, a clinical overview

“…Heterozygous mutations in the HNF1B gene are associated with a multi-system disorder and considered to be the most common genetic cause of congenital anomalies of the kidney and urinary tract (CAKUT) (reviewed in [47, 48]). The HNF1B gene is situated in a region susceptible for genomic rearrangements, resulting in a high frequency of large deletions and de novo gene defects [47].…”

Renal development in the fetus and premature infant

“…Autosomal dominant mutations in HNF1B are the most frequent monogenic etiology of CAKUT [60,80,81]. HNF1B is a transcription factor that contributes to both ureter development and nephron segmentation [82–84].…”

Hepatocyte Nuclear Factor 1-β Gene Mutation: Brief Report and Review of Hepatic Involvement

“…HNF1β is involved in the transcriptional and functional regulations of the liver, biliary system, kidney, urogenital tract, and pancreatic β-cells [3,4]. Defects of this gene have been described in a small subgroup of patients with MODY, including point mutations and whole gene deletions, with the majority being de novo whole gene mutations [5,6].…”

“…The phenotypical spectrum of individuals with HNF1β mutations varies widely. The major features are MODY and cystic renal disease, however, agenesis of the pancreas, urogenital malformations, hyperparathyroidism, gout, cognitive delay, autism spectrum disorder, and hepatic disorders have also been described [3,4].…”