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Hepatocyte nuclear factor-1beta (HNF1B) is a homeodomain transcription factor critical for renal and pancreatic developmental programs. Heterozygous loss-of-function variants in HNF1B underlie an autosomal dominant multi-system disorder characterized by congenital renal cysts, tubular dysplasia, and maturity-onset diabetes of the young type 5 (MODY5), collectively termed renal cysts and diabetes syndrome (RCAD). Patients may present with varying combinations of renal cystic disease, tubular electrolyte wasting, pancreatic hypoplasia, genital tract malformations, and early-onset diabetes, reflecting pleiotropic roles of HNF1B in organogenesis.
Clinical penetrance of HNF1B variants is high with diabetes manifesting in adolescence or early adulthood, and renal anomalies detectable by prenatal ultrasonography in over 60% of carriers. Hypomagnesemia and hyperuricemia are frequent electrolyte disturbances, whereas exocrine pancreatic insufficiency and liver dysfunction can emerge across the lifespan. HNF1B-related disease exhibits incomplete but significant intrafamilial phenotypic variability, with de novo variants reported in 40–66% of cases. Genetic testing should be considered in patients with congenital kidney anomalies plus diabetes or unexplained liver tests.
Genetic association between HNF1B and RCAD is well established. An initial case described a pediatric renal transplant recipient with steroid-induced diabetes revealing a novel exon 1 frameshift variant c.206_207del (p.His69fsTer) among 12 kindreds at the time (PMID:12460054). A comprehensive review later catalogued 106 unique HNF1B mutations in 236 mutation-positive families, encompassing gross deletions (34%), missense (31%), frameshift (15%), nonsense (11%), and splice-site changes (8%) (PMID:25700310). Autosomal dominant inheritance with both familial segregation and frequent de novo occurrence underscores robust genetic evidence.
Functional and experimental data corroborate haploinsufficiency as the principal pathogenic mechanism. In vitro assays demonstrate that truncating and missense HNF1B alleles impair DNA binding or coactivator recruitment, leading to reduced transactivation of key renal and pancreatic target genes such as PDX1 and FXYD2. HNF1B frameshift and deletion mutants exert loss-of-function with no dominant-negative activity in beta-cell lines and HEK293 cells. Animal models in Xenopus and zebrafish recapitulate renal cyst formation, pancreatic hypoplasia, and gut patterning defects upon hnf1b knockdown or expression of human mutant alleles (PMID:11731484).
No substantial conflicting evidence has been reported; all published variants co-segregate with disease traits, and no benign polymorphisms have been convincingly linked to causal RCAD. Together, genetic, functional, and in vivo studies over >20 years support a definitive gene-disease relationship. Clinical utility is high as molecular diagnosis guides surveillance for renal, endocrine, and urogenital complications and enables family screening.
Key take-home: HNF1B haploinsufficiency is a definitive cause of renal cysts and diabetes syndrome, and early genetic testing is essential for personalized management and prevention of multi-system morbidities.
Gene–Disease AssociationDefinitive236 mutation-positive families, extensive segregation & functional concordance Genetic EvidenceStrong236 families with diverse variant types in autosomal dominant inheritance cap reached Functional EvidenceStrongMultiple in vitro assays and animal models demonstrate haploinsufficiency mechanism |