Mutations in the hepatocyte nuclear factor-1beta gene are associated with familial hypoplastic glomerulocystic kidney disease

Abstract

Familial glomerulocystic kidney disease (GCKD) is a dominantly inherited condition characterized by glomerular cysts and variable renal size and function; the molecular genetic etiology is unknown. Mutations in the gene encoding hepatocyte nuclear factor (HNF)-1beta have been associated with early-onset diabetes and nondiabetic renal disease-particularly renal cystic disease. We investigated a possible role for the HNF-1beta gene in four unrelated GCKD families and identified mutations in two families: a nonsense mutation in exon 1 (E101X) and a frameshift mutation in exon 2 (P159fsdelT). The family members with HNF-1beta gene mutations had hypoplastic GCKD and early-onset diabetes or impaired glucose tolerance. We conclude that there is genetic heterogeneity in familial GCKD and that the hypoplastic subtype is a part of the clinical spectrum of the renal cysts and diabetes syndrome that is associated with HNF-1beta mutations.

Figure 1

Pedigrees of two families with HNF-1β mutations. Roman numerals on left of the figure indicate generation number, and the numbers below the symbols indicate individuals within that generation. The HNF-1β genotype of each individual tested is indicated below the symbol: N, =normal, M = mutated allele. Blackened lower left quadrant = impaired glucose tolerance; blackened lower and upper left quadrants = diabetes; blackened upper right quadrant = renal cysts; blackened lower right quadrant = renal impairment; diamond symbol containing a number = no. of siblings unavailable for testing.