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HNF1beta mutation

J M Bailey, A M Hendley, K J Lafaro, M A Pruski, N C Jones, J Alsina, M Younes, A Maitra, F McAllister, C A Iacobuzio-Donahue, S D Leach
Pancreatic cancer is one of the most lethal malignancies, with virtually all patients eventually succumbing to their disease. Mutations in p53 have been documented in >50% of pancreatic cancers. Owing to the high incidence of p53 mutations in PanIN 3 lesions and pancreatic tumors, we interrogated the comparative ability of adult pancreatic acinar and ductal cells to respond to oncogenic Kras and mutant Tp53(R172H) using Hnf1b:CreER(T2) and Mist1:CreER(T2) mice. These studies involved co-activation of a membrane-tethered GFP lineage label, allowing for direct visualization and isolation of cells undergoing Kras and mutant p53 activation...
August 11, 2016: Oncogene
Laurence Heidet, Stéphane Decramer, Audrey Pawtowski, Vincent Morinière, Flavio Bandin, Bertrand Knebelmann, Anne-Sophie Lebre, Stanislas Faguer, Vincent Guigonis, Corinne Antignac, Rémi Salomon
BACKGROUND AND OBJECTIVES: Hepatocyte nuclear factor 1beta (HNF1beta) is a transcription factor that is critical for the development of kidney and pancreas. In humans, mutations in HNF1B lead to congenital anomalies of the kidney and urinary tract, pancreas atrophy, and maturity-onset diabetes of the young type 5 and genital malformations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We report HNF1B screening in a cohort of 377 unrelated cases with various kidney phenotypes (hyperechogenic kidneys with size not more than +3 SD, multicystic kidney disease, renal agenesis, renal hypoplasia, cystic dysplasia, or hyperuricemic tubulointerstitial nephropathy not associated with UMOD mutation)...
June 2010: Clinical Journal of the American Society of Nephrology: CJASN
J-P Le Berre, C Bellanné-Chantelot, L Bordier, C Garcia, O Dupuy, H Mayaudon, B Bauduceau
A 55-year-old woman presented with a recent diabetes mellitus associated with pancreatic and renal malformations. This atypical diabetes raised the possibility of maturity onset diabetes of the young (MODY) and a genetic research was performed. These malformations led to MODY5 diagnosis that was confirmed by the presence of HNF1beta gene mutation.
June 2010: La Revue de Médecine Interne
Makiko Nakayama, Kandai Nozu, Yuki Goto, Koichi Kamei, Shuichi Ito, Hidenori Sato, Mitsuru Emi, Koichi Nakanishi, Shigeru Tsuchiya, Kazumoto Iijima
Hepatocyte nuclear factor 1beta (HNF1beta) abnormalities have been recognized to cause congenital anomalies of the kidney and urinary tract (CAKUT), predominantly affecting bilateral renal malformations. To further understand the spectrum of HNF1beta related phenotypes, we performed HNF1B gene mutation and deletion analyses in Japanese patients with renal hypodysplasia (n = 31), unilateral multicystic dysplastic kidney (MCDK; n = 14) and others (n = 5). We identified HNF1B alterations in 5 out of 50 patients (10%)...
June 2010: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Joan-Marc Servitja, Miguel Pignatelli, Miguel Angel Maestro, Carina Cardalda, Sylvia F Boj, Juanjo Lozano, Enrique Blanco, Amàlia Lafuente, Mark I McCarthy, Lauro Sumoy, Roderic Guigó, Jorge Ferrer
Heterozygous HNF1A mutations cause pancreatic-islet beta-cell dysfunction and monogenic diabetes (MODY3). Hnf1alpha is known to regulate numerous hepatic genes, yet knowledge of its function in pancreatic islets is more limited. We now show that Hnf1a deficiency in mice leads to highly tissue-specific changes in the expression of genes involved in key functions of both islets and liver. To gain insights into the mechanisms of tissue-specific Hnf1alpha regulation, we integrated expression studies of Hnf1a-deficient mice with identification of direct Hnf1alpha targets...
June 2009: Molecular and Cellular Biology
Louise Chappell, Shaun Gorman, Fiona Campbell, Sian Ellard, Gillian Rice, Angus Dobbie, Yanick Crow
We report a patient born to consanguineous parents as a further example of a recently described phenotype comprising neonatal diabetes, intestinal atresias and gall bladder agenesis. Other reports have described cases with overlapping patterns including malrotation, biliary atresia and pancreatic hypoplasia (e.g. as described by Martínez-Frías). We propose that these cases may represent variations of the same syndrome. It is likely that this disorder is inherited as an autosomal recessive trait. Our case is the first to have neonatal diabetes without a demonstrable structural pancreatic abnormality, showing that a deficit in pancreatic function is involved...
July 1, 2008: American Journal of Medical Genetics. Part A
Karin Dudziak, Nima Mottalebi, Sabine Senkel, Emma L Edghill, Stefan Rosengarten, Magdalena Roose, Coralie Bingham, Sian Ellard, Gerhart U Ryffel
Heterozygous mutations of the tissue-specific transcription factor hepatocyte nuclear factor (HNF)1beta, cause maturity onset diabetes of the young (MODY5) and kidney anomalies including agenesis, hypoplasia, dysplasia and cysts. Because of these renal anomalies, HNF1beta is classified as a CAKUT (congenital anomalies of the kidney and urinary tract) gene. We searched for human fetal kidney proteins interacting with the N-terminal region of HNF1beta using a bacterial two-hybrid system and identified five novel proteins along with the known partner DCoH...
July 2008: Kidney International
Paul Winyard, Lyn S Chitty
Dysplastic kidneys are common malformations affecting up to 1 in 1000 of the general population. They are part of the spectrum of Congenital Abnormalities of the Kidney and Urinary Tract (CAKUT) and an increasing number of children are being diagnosed on antenatal ultrasound. In the past, these patients may not have been detected until adulthood following investigation for other illness, or even as incidental findings at post mortem, unless there was severe bilateral dysplasia leading to Potter's sequence or renal failure in childhood...
June 2008: Seminars in Fetal & Neonatal Medicine
Takami Saji, Ryota Kikuchi, Hiroyuki Kusuhara, Insook Kim, Frank J Gonzalez, Yuichi Sugiyama
Organic anion transporter 1 (OAT1/SLC22A6) is predominantly expressed in the proximal tubules of the kidney. Cumulative studies have shown its critical role in the tubular secretion of a variety of organic anions, including several clinically important drugs. In addition, OAT1 is also involved in the pharmacological effect of diuretics and the nephrotoxicity of antiviral drugs. In contrast to these functional characterizations, the regulatory mechanism of OAT1 expression is poorly understood. It was recently demonstrated that the expression of Oat1 was markedly reduced in the kidneys of hepatocyte nuclear factor 1alpha (Hnf1alpha)-null mice...
February 2008: Journal of Pharmacology and Experimental Therapeutics
Peng Lu, Geun Bae Rha, Young-In Chi
HNF1beta is an atypical POU transcription factor that participates in a hierarchical network of transcription factors controlling the development and proper function of vital organs such as liver, pancreas, and kidney. Many inheritable mutations on HNF1beta are the monogenic causes of diabetes and several kidney diseases. To elucidate the molecular mechanism of its function and the structural basis of mutations, we have determined the crystal structure of human HNF1beta DNA binding domain in complex with a high-affinity promoter...
October 30, 2007: Biochemistry
Miguel Angel Maestro, Carina Cardalda, Sylvia F Boj, Reini F Luco, Joan Marc Servitja, Jorge Ferrer
Mutations in the genes encoding transcriptional regulators HNF1beta (TCF2), HNF1alpha (TCF1), and HNF4alpha cause autosomal dominant diabetes (also known as maturity-onset diabetes of the young). Herein, we review what we have learnt during recent years concerning the functions of these regulators in the developing and adult pancreas. Mouse studies have revealed that HNF1beta is a critical regulator of a transcriptional network that controls the specification, growth, and differentiation of the embryonic pancreas...
2007: Endocrine Development
Kei Fujimoto, Takashi Sasaki, Yoshito Hiki, Masami Nemoto, Yasunori Utsunomiya, Takashi Yokoo, Nozomu Nakai, Toya Ohashi, Tatsuo Hosoya, Yoshikatsu Eto, Naoko Tajima
Maturity-onset diabetes of the young type 5 (MODY5) is caused by mutation of hepatocyte nuclear factor 1beta (HNF1 beta) (TCF2) gene, resulting in a wide range of phenotypes including diabetes and renal abnormalities, but little is known about the pathogenesis of the clinical spectrum. We describe a 27-year-old Japanese male with the MODY phenotype including an atrophic kidney and multiple renal cysts. Genetic analysis revealed the patient to be heterozygous for a nonsense mutation in codon 276 of the HNF1beta gene (CGA or Arginine to TGA or stop codon; R276X)...
December 2007: Endocrine Journal
Julius Gudmundsson, Patrick Sulem, Valgerdur Steinthorsdottir, Jon T Bergthorsson, Gudmar Thorleifsson, Andrei Manolescu, Thorunn Rafnar, Daniel Gudbjartsson, Bjarni A Agnarsson, Adam Baker, Asgeir Sigurdsson, Kristrun R Benediktsdottir, Margret Jakobsdottir, Thorarinn Blondal, Simon N Stacey, Agnar Helgason, Steinunn Gunnarsdottir, Adalheidur Olafsdottir, Kari T Kristinsson, Birgitta Birgisdottir, Shyamali Ghosh, Steinunn Thorlacius, Dana Magnusdottir, Gerdur Stefansdottir, Kristleifur Kristjansson, Yu Bagger, Robert L Wilensky, Muredach P Reilly, Andrew D Morris, Charlotte H Kimber, Adebowale Adeyemo, Yuanxiu Chen, Jie Zhou, Wing-Yee So, Peter C Y Tong, Maggie C Y Ng, Torben Hansen, Gitte Andersen, Knut Borch-Johnsen, Torben Jorgensen, Alejandro Tres, Fernando Fuertes, Manuel Ruiz-Echarri, Laura Asin, Berta Saez, Erica van Boven, Siem Klaver, Dorine W Swinkels, Katja K Aben, Theresa Graif, John Cashy, Brian K Suarez, Onco van Vierssen Trip, Michael L Frigge, Carole Ober, Marten H Hofker, Cisca Wijmenga, Claus Christiansen, Daniel J Rader, Colin N A Palmer, Charles Rotimi, Juliana C N Chan, Oluf Pedersen, Gunnar Sigurdsson, Rafn Benediktsson, Eirikur Jonsson, Gudmundur V Einarsson, Jose I Mayordomo, William J Catalona, Lambertus A Kiemeney, Rosa B Barkardottir, Jeffrey R Gulcher, Unnur Thorsteinsdottir, Augustine Kong, Kari Stefansson
We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1...
August 2007: Nature Genetics
Michael P Hunter, Christine M Wilson, Xiaobing Jiang, Rong Cong, Hemaxi Vasavada, Klaus H Kaestner, Clifford W Bogue
Hhex is required for early development of the liver. A null mutation of Hhex results in a failure to form the liver bud and embryonic lethality. Therefore, Hhex null mice are not informative as to whether this gene is required during later stages of hepatobiliary morphogenesis. To address this question, we derived Hhex conditional null mice using the Cre-loxP system and two different Cre transgenics (Foxa3-Cre and Alfp-Cre). Deletion of Hhex in the hepatic diverticulum (Foxa3-Cre;Hhex(d2,3/-)) led to embryonic lethality and resulted in a small and cystic liver with loss of Hnf4alpha and Hnf6 expression in early hepatoblasts...
August 15, 2007: Developmental Biology
Dagan Jenkins, Maria Bitner-Glindzicz, Louise Thomasson, Sue Malcolm, Stephanie A Warne, Sally A Feather, Sarah E Flanagan, Sian Ellard, Coralie Bingham, Lane Santos, Mark Henkemeyer, Andrew Zinn, Linda A Baker, Duncan T Wilcox, Adrian S Woolf
OBJECTIVES: 'Persistent cloaca' is a severe malformation affecting females in which the urinary, genital and alimentary tracts share a single conduit. Previously, a Uroplakin IIIA (UPIIIA) mutation was reported in one individual with persistent cloaca, and UPIIIA, Sonic Hedgehog (SHH), Ephrin B2 (EFNB2) and Hepatocyte Nuclear Factor 1beta (HNF1beta) are expressed during the normal development of organs that are affected in this condition. HNF1beta mutations have been associated with uterine malformations in humans, and mutations of genes homologous to human SHH or EFNB2 cause persistent cloaca in mice...
February 2007: Journal of Pediatric Urology
Limei Liu, Hiroto Furuta, Asako Minami, Taishan Zheng, Weiping Jia, Kishio Nanjo, Kunsan Xiang
OBJECTIVES: During examining the prevalence of mutations in NeuroD1/BETA2 gene in Chinese early-onset type 2 diabetic probands, a novel missense mutation, Ser159Pro in a potential MODY family was identified. To investigate the role of the mutation in early-onset diabetes, we studied its transcriptional activity on human insulin gene and clinical characteristics of the family with the mutation. METHODS: Bi-directional sequencing of NeuroD1/BETA2 was performed in 85 early-onset type 2 diabetic probands without mutations in HNF4alpha, glucokinase, HNF1alpha, IPF-1 and HNF1beta genes, 95 late-onset type 2 diabetics with strong diabetic history and 87 non-diabetic control subjects...
September 2007: Molecular and Cellular Biochemistry
F Lehner, U Kulik, J Klempnauer, J Borlak
The molecular causes leading to secondary liver malignancies are unknown. Here we report regulation of major hepatic nuclear factors in human colorectal liver metastases and primary colonic cancer. Notably, the genes coding for HNF6, HNF1beta, and C/EBPgamma were selectively regulated in liver metastases. We therefore studied protein expression of regulated transcription factors and found unacetylated HNF6 to be a hallmark of colorectal liver metastases. For its known interaction with HNF6, we investigated expression of FOXA2, which we found to be specifically induced in colorectal liver metastases...
May 2007: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
S Gad, S H Lefèvre, S K Khoo, S Giraud, A Vieillefond, V Vasiliu, S Ferlicot, V Molinié, Y Denoux, N Thiounn, Y Chrétien, A Méjean, M Zerbib, G Benoît, J M Hervé, G Allègre, B Bressac-de Paillerets, B T Teh, S Richard
BHD, TP53, and HNF1beta on chromosome 17 were studied in 92 cases of renal cell carcinoma (46 chromophobe, 19 clear cell, 18 oncocytoma, and nine papillary). Six, thirteen, and zero cases had, respectively BHD, TP53, and HNF1beta mutations, (84% mutations involved chromophobe), suggesting a role for BHD and TP53 in chromophobe subtype.
January 29, 2007: British Journal of Cancer
Hannah J Welters, Sabine Senkel, Ludger Klein-Hitpass, Silke Erdmann, Heike Thomas, Lorna W Harries, Ewan R Pearson, Coralie Bingham, Andrew T Hattersley, Gerhart U Ryffel, Noel G Morgan
Mutations in the gene encoding hepatocyte nuclear factor (HNF)1beta result in maturity-onset diabetes of the young-(MODY)5, by impairing insulin secretory responses and, possibly, by reducing beta-cell mass. The functional role of HNF1beta in normal beta-cells is poorly understood; therefore, in the present study, wild-type (WT) HNF1beta, or one of two naturally occurring MODY5 mutations (an activating mutation, P328L329del, or a dominant-negative form, A263insGG) were conditionally expressed in the pancreatic beta-cell line, insulin-1 (INS-1), and the functional consequences examined...
July 2006: Journal of Endocrinology
Cécile Haumaitre, Mélanie Fabre, Sarah Cormier, Clarisse Baumann, Anne-Lise Delezoide, Silvia Cereghini
Heterozygous mutations in the HNF1beta/vHNF1/TCF2 gene cause maturity-onset diabetes of the young (MODY5), associated with severe renal disease and abnormal genital tract. Here, we characterize two fetuses, a 27-week male and a 31.5-week female, carrying novel mutations in exons 2 and 7 of HNF1beta, respectively. Although these mutations were predicted to have different functional consequences, both fetuses displayed highly similar phenotypes. They presented one of the most severe phenotypes described in HNF1beta carriers: bilateral enlarged polycystic kidneys, severe pancreas hypoplasia and abnormal genital tract...
August 1, 2006: Human Molecular Genetics
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