Hepatocyte nuclear factor-1 beta: A new kindred with renal cysts and diabetes and gene expression in normal human development

The hepatocyte nuclear factor-1 beta (HNF-1 beta) transcription factor cont rols endoderm development. Human mutations cause early-onset diabetes melli tus and have recently been associated with dysplastic, hypoplastic, and glo merulocystic kidneys. A new kindred with this "renal cysts and diabetes" sy ndrome is described, and nephrogenic HNF-1 beta expression is defined. The proband had congenital cystic kidneys: over the next 12 yr, his renal funct ion was impaired, but he was normoglycemic. His mother developed diabetes d uring pregnancy: renal ultrasonography at age 24 yr was normal, but she sub sequently developed cysts. Both subjects have a heterozygous frameshift mut ation in HNF-1 beta that results from a 1-bp insertion in exon 5 (Y352fsins A). When reverse-transcription PCR and in situ hybridization were used, HNF -1 beta mRNA was detected in normal human metanephroi, with the highest lev els of transcripts localized to fetal medullary and cortical collecting duc ts and low levels of expression in nephrogenic cortex mesenchyme, primitive nephron tubules, and immature glomeruli. These results constitute the firs t demonstration of HNF-1 beta expression during human nephrogenesis and emp hasize a disease spectrum associated with HNF-1 beta mutation.