Mutation of hepatocyte nuclear factor-1beta inhibits Pkhd1 gene expression and produces renal cysts in mice.

Hepatocyte nuclear factor-1beta (HNF-1beta) is a Pit-1, Oct-1/2, UNC-86 (POU)/homeodomain-containing transcription factor that regulates tissue-specific gene expression in the liver, kidney, and other organs. Humans with autosomal dominant mutations of HNF-1beta develop maturity-onset diabetes of the young type 5 (MODY5) and congenital cystic abnormalities of the kidney. Autosomal recessive polycystic kidney disease (ARPKD) is an inherited cystic disorder that produces renal failure in infants and children and is caused by mutations of PKHD1. The proximal promoter of the mouse Pkhd1 gene contains an evolutionarily conserved HNF-1-binding site that is located near a region of deoxyribonuclease hypersensitivity. HNF-1beta and the structurally related HNF-1alpha bind specifically to the Pkhd1 promoter and stimulate gene transcription. Mutations of the HNF-1 site or expression of a dominant-negative HNF-1beta mutant inhibit Pkhd1 promoter activity in transfected cells. Transgenic mice expressing a dominant-negative HNF-1beta mutant under the control of a kidney-specific promoter develop renal cysts, similarly to humans with MODY5. Pkhd1 transcripts are absent in the cells lining the cysts but are present in morphologically normal surrounding tubules. These studies identify a link between two cystic disease genes, HNF1beta (MODY5) and PKHD1 (ARPKD). HNF-1beta directly regulates the transcription of Pkhd1, and inhibition of PKHD1 gene expression may contribute to the formation of renal cysts in humans with MODY5.

[1]  G. Crabtree,et al.  A variant nuclear protein in dedifferentiated hepatoma cells binds to the same functional sequences in the beta fibrinogen gene promoter as HNF‐1. , 1988, The EMBO journal.

[2]  G. Crabtree,et al.  HNF-1 alpha and HNF-1 beta (vHNF-1) share dimerization and homeo domains, but not activation domains, and form heterodimers in vitro. , 1991, Genes & development.

[3]  R. Cortese,et al.  LFB1 and LFB3 homeoproteins are sequentially expressed during kidney development. , 1992, Development.

[4]  K. Zerres,et al.  Autosomal recessive polycystic kidney disease , 1992, The clinical investigator.

[5]  J. Calvet.  Injury and development in polycystic kidney disease. , 1994, Current opinion in nephrology and hypertension.

[6]  M. Yaniv,et al.  Hepatocyte Nuclear Factor 1 Inactivation Results in Hepatic Dysfunction, Phenylketonuria, and Renal Fanconi Syndrome , 1996, Cell.

[7]  Hiroyuki Kuroki,et al.  Mutation in hepatocyte nuclear factor–1β gene (TCF2) associated with MODY , 1997, Nature Genetics.

[8]  J. Takeda,et al.  Frameshift Mutation, A263fsinsGG, in the Hepatocyte Nuclear Factor-1β Gene Associated With Diabetes and Renal Dysfunction , 1998, Diabetes.

[9]  M. Yaniv,et al.  Expression of the vHNF1/HNF1β homeoprotein gene during mouse organogenesis , 1999, Mechanisms of Development.

[10]  S. Cereghini,et al.  Variant hepatocyte nuclear factor 1 is required for visceral endoderm specification. , 1999, Development.

[11]  M. Yaniv,et al.  Essential role for the homeoprotein vHNF1/HNF1beta in visceral endoderm differentiation. , 1999, Development.

[12]  K. Yamagata,et al.  Loss-of-function and Dominant-negative Mechanisms Associated with Hepatocyte Nuclear Factor-1β Mutations in Familial Type 2 Diabetes Mellitus* , 1999, The Journal of Biological Chemistry.

[13]  P. Igarashi,et al.  Ksp-cadherin gene promoter. I. Characterization and renal epithelial cell-specific activity. , 1999, The American journal of physiology.

[14]  M. Pontoglio,et al.  Hepatocyte nuclear factor 1, a transcription factor at the crossroads of glucose homeostasis. , 2000, Journal of the American Society of Nephrology : JASN.

[15]  A. Hattersley,et al.  The mutated human gene encoding hepatocyte nuclear factor 1beta inhibits kidney formation in developing Xenopus embryos. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  A. Woolf,et al.  Diabetes, genes, and kidney development. , 2000, Kidney international.

[17]  A. Hattersley,et al.  Mutations in the hepatocyte nuclear factor-1beta gene are associated with familial hypoplastic glomerulocystic kidney disease. , 2001, American journal of human genetics.

[18]  M. Pfaffl,et al.  A new mathematical model for relative quantification in real-time RT-PCR. , 2001, Nucleic acids research.

[19]  N. Hopkins,et al.  vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain. , 2001, Genes & development.

[20]  A. Woolf,et al.  Recent insights into kidney diseases associated with glomerular cysts , 2002, Pediatric Nephrology.

[21]  B. Godley,et al.  Oxidant and antioxidant modulation of chloride channels expressed in human retinal pigment epithelium. , 2002, American journal of physiology. Cell physiology.

[22]  Vicente E. Torres,et al.  The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein , 2002, Nature Genetics.

[23]  L. Gresh,et al.  Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1beta. , 2002, Development.

[24]  Z. Zhao,et al.  A novel gene encoding a TIG multiple domain protein is a positional candidate for autosomal recessive polycystic kidney disease. , 2002, Genomics.

[25]  P. Igarashi,et al.  Regulation of kidney-specific Ksp-cadherin gene promoter by hepatocyte nuclear factor-1beta. , 2002, American journal of physiology. Renal physiology.

[26]  P. Igarashi,et al.  A minimal Ksp-cadherin promoter linked to a green fluorescent protein reporter gene exhibits tissue-specific expression in the developing kidney and genitourinary tract. , 2002, Journal of the American Society of Nephrology : JASN.

[27]  E. Avner,et al.  PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. , 2002, American journal of human genetics.

[28]  P. Igarashi,et al.  Epithelial-specific Cre/lox recombination in the developing kidney and genitourinary tract. , 2002, Journal of the American Society of Nephrology : JASN.

[29]  G. Rizzoni,et al.  Renal cysts and diabetes syndrome linked to mutations of the hepatocyte nuclear factor-1 beta gene: description of a new family with associated liver involvement. , 2002, American Journal of Kidney Diseases.

[30]  E. Avner,et al.  Identification and characterization of Pkhd1, the mouse orthologue of the human ARPKD gene. , 2002, Journal of the American Society of Nephrology : JASN.

[31]  P. Igarashi,et al.  Genetics and pathogenesis of polycystic kidney disease. , 2002, Journal of the American Society of Nephrology : JASN.

[32]  Roser Torra,et al.  A complete mutation screen of PKHD1 in autosomal-recessive polycystic kidney disease (ARPKD) pedigrees. , 2003, Kidney international.

[33]  N. Murcia,et al.  Delayed cystogenesis and increased ciliogenesis associated with the re-expression of polaris in Tg737 mutant mice. , 2003, Kidney international.

[34]  L. Guay-Woodford,et al.  Autosomal recessive polycystic kidney disease: the clinical experience in North America. , 2003, Pediatrics.

[35]  N. LaRusso,et al.  Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. , 2003, Human molecular genetics.

[36]  Carsten Bergmann,et al.  Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1). , 2003, Journal of the American Society of Nephrology : JASN.

[37]  Carsten Bergmann,et al.  Milder presentation of recessive polycystic kidney disease requires presence of amino acid substitution mutations. , 2003, Journal of the American Society of Nephrology : JASN.

[38]  A. Hattersley,et al.  Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1beta gene mutation. , 2003, Kidney international.

[39]  A. Hattersley,et al.  Distinct molecular and morphogenetic properties of mutations in the human HNF1beta gene that lead to defective kidney development. , 2003, Journal of the American Society of Nephrology : JASN.

[40]  L. Goldstein,et al.  Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Andreas Reimann,et al.  A transcriptional network in polycystic kidney disease , 2004, The EMBO journal.