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Sian Ellard - One of the best experts on this subject based on the ideXlab platform.
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HNF1B associated renal and extra renal disease an expanding clinical spectrum
Nature Reviews Nephrology, 2015Co-Authors: Rhian L Clissold, Sian Ellard, Andrew T Hattersley, Alexander J Hamilton, Coralie BinghamAbstract:Heterozygous mutations in the gene that encodes the transcription factor hepatocyte nuclear factor 1β (HNF1B) represent the most common known monogenic cause of developmental kidney disease. Renal cysts are the most frequently detected feature of HNF1B-associated kidney disease; however, other structural abnormalities, including single kidneys and renal hypoplasia, and electrolyte abnormalities can also occur. Extra-renal phenotypes might also be observed; consequently, HNF1B-associated disease is considered a multi-system disorder. Other clinical features include early-onset diabetes mellitus, pancreatic hypoplasia, genital tract malformations, abnormal liver function and early-onset gout. Heterozygous mutations in the coding region or splice sites of HNF1B, and complete gene deletion, each account for ∼50% of all cases of HNF1B-associated disease, respectively, and often arise spontaneously. There is no clear genotype-phenotype correlation, consistent with haploinsufficiency as the disease mechanism. Data from animal models suggest that HNF1B has an important function during several stages of nephrogenesis; however, the precise signalling pathways remain to be elucidated. This Review discusses the genetics and molecular pathways that lead to disease development, summarizes the reported renal and extra-renal phenotypes, and identifies areas for future research in HNF1B-associated disease.
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HNF1B deletions in patients with young onset diabetes but no known renal disease
Diabetic Medicine, 2013Co-Authors: Emma L Edghill, Andrew T Hattersley, Richard A Oram, Maggie Shepherd, Karen Stals, Sian EllardAbstract:Diabet. Med. 30, 114–117 (2013) Abstract Aims Hepatocyte nuclear factor 1β (HNF1B) mutations cause a syndrome of renal cysts and diabetes, with whole gene deletions accounting for approximately 50% of cases. The severity of the renal phenotype is variable, from enlarged cystic kidneys incompatible with life to normal renal development and function. We investigated the prevalence of HNF1B deletions in patients with diabetes but no known renal disease. Methods We tested 461 patients with familial diabetes diagnosed before 45 years, including 258 probands who met clinical criteria for maturity-onset diabetes of the young (two generations affected and at least one family member diagnosed under 25 years). A fluorescent polymerase chain reaction assay was used to analyse two intragenic polymorphic HNF1B markers and identify heterozygous patients who therefore did not have whole gene deletions. Those patients homozygous for both markers were then tested for an HNF1B deletion using multiplex ligation-dependent probe amplification. Results Heterozygous HNF1B intragenic polymorphisms were identified in 337/461 subjects. Multiplex ligation-dependent probe amplification analysis showed an HNF1B gene deletion in three of the remaining 124 probands, all of whom met the criteria for maturity-onset diabetes of the young. Testing of their relatives identified three additional deletion carriers and ultrasound scanning showed renal developmental abnormalities in three of these six patients. Conclusions We estimate that HNF1B mutations account for < 1% of cases of maturity-onset diabetes of the young. Although HNF1B mutations are a rare cause of diabetes in the absence of known renal disease, a genetic diagnosis of renal cysts and diabetes syndrome is important as it raises the possibility of subclinical renal disease and the 50% risk of renal cysts and diabetes syndrome in the patient’s offspring.
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high sensitivity crp discriminates hnf1a mody from other subtypes of diabetes
Diabetes Care, 2011Co-Authors: Timothy J. Mcdonald, Sian Ellard, Beverley M. Shields, Jane Lawry, Katharine R. Owen, Anna L. Gloyn, Andrew T HattersleyAbstract:OBJECTIVE Maturity-onset diabetes of the young (MODY) as a result of mutations in hepatocyte nuclear factor 1-α ( HNF1A ) is often misdiagnosed as type 1 diabetes or type 2 diabetes. Recent work has shown that high-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY than type 1 diabetes, type 2 diabetes, or glucokinase (GCK)-MODY. We aim to replicate these findings in larger numbers and other MODY subtypes. RESEARCH DESIGN AND METHODS hs-CRP levels were assessed in 750 patients (220 HNF1A , 245 GCK , 54 HNF4-α [ HNF4A ], 21 HNF1-β ( HNF1B ), 53 type 1 diabetes, and 157 type 2 diabetes). RESULTS hs-CRP was lower in HNF1A-MODY (median interquartile [IQR] 0.3 [0.1–0.6] mg/L) than type 2 diabetes (median [IQR] 1.40 [0.60–3.45] mg/L; P < 0.001) and type 1 diabetes (median [IQR] 1.10 [0.50–1.85] mg/L; P < 0.001), HNF4A-MODY (median [IQR] 1.45 [0.46–2.88] mg/L; P < 0.001), GCK-MODY (median [IQR] 0.60 [0.30–1.80] mg/L; P < 0.001), and HNF1B-MODY (median [IQR] 0.60 [0.10–2.8] mg/L; P = 0.07). hs-CRP discriminated HNF1A-MODY from type 2 diabetes with hs-CRP <0.75 mg/L showing 79% sensitivity and 70% specificity (receiver operating characteristic area under curve = 0.84). CONCLUSIONS hs-CRP levels are lower in HNF1A-MODY than other forms of diabetes and may be used as a biomarker to select patients for diagnostic HNF1A genetic testing.
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mutations in the hepatocyte nuclear factor 1β HNF1B gene are common with combined uterine and renal malformations but are not found with isolated uterine malformations
American Journal of Obstetrics and Gynecology, 2010Co-Authors: Richard A Oram, Sian Ellard, Emma L Edghill, Jenny Blackman, Miles J O Taylor, Tracey Kay, Sarah E Flanagan, Ida Ismailpratt, Sarah M Creighton, Andrew T HattersleyAbstract:Objective Congenital uterine abnormalities are common and may be associated with developmental renal abnormalities. Mutations of the hepatocyte nuclear factor-1β ( HNF1B) gene are associated with renal and uterine abnormalities. We aimed to study the role of HNF1B mutations in a cohort with congenital uterine abnormalities. Study Design We tested 108 probands with uterine abnormalities for HNF1B mutations. We collected clinical information from patient records. Results Nine of 108 women (8%) had a mutation or deletion in the HNF1B gene. Abnormal HNF1B was found in 18% of the 50 probands who had both uterine and renal abnormalities but in none of the 58 women with isolated uterine abnormalities. Conclusion Mutations of the HNF1B gene are found in women with both uterine and renal abnormalities but are rare in isolated uterine abnormalities. We suggest that HNF1B testing should be performed in patients with both renal and uterine abnormalities, but not in patients with isolated uterine abnormalities.
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partial and whole gene deletion mutations of the gck and hnf1a genes in maturity onset diabetes of the young
Diabetologia, 2007Co-Authors: Sian Ellard, Amanda Stride, K Thomas, Emma L Edghill, Martina Owens, L Ambye, J Cropper, J Little, Mark W J Strachan, Betul ErsoyAbstract:Aims/hypothesis Heterozygous mutations of glucokinase (GCK) and hepatocyte nuclear factor-1 alpha (HNF1A; also known as hepatic transcription factor 1 [TCF1]) genes are the most common cause of MODY. Genomic deletions of the HNF1B (also known as TCF2) gene have recently been shown to account for one third of mutations causing renal cysts and diabetes syndrome. We investigated the prevalence of partial and whole gene deletions in UK patients meeting clinical criteria for GCK or HNF-1α/-4α MODY and in whom no mutation had been identified by sequence analysis.
Stanislas Faguer - One of the best experts on this subject based on the ideXlab platform.
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calcineurin inhibitors down regulate hnf 1β and may affect the outcome of HNF1B patients after renal transplantation
Archives De Pediatrie, 2016Co-Authors: Stephane Decramer, Stanislas Faguer, J P SchanstraAbstract:Background Patients with HNF1B mutations develop progressive chronic renal failure, diabetes mellitus (40–50%) and liver tests abnormalities (40–70%). In HNF1B patients who reach end-stage renal disease, single kidney (SKT) or combined kidney-pancreas transplantation (KPT) can be considered. Methods A retrospective multicenter study including 18 HNF1B patients receiving SKT or KPT, and in vitro experiments including the characterization of the HNF1B expression after calcineurin inhibitor (CNI) exposure. Results Following SKT, 50% of the HNF1B patients develop early post-transplantation diabetes mellitus (PTDM), while 40% experience new-onset or severe worsening of pre-existing abnormalities of liver tests, including severe cholestasis. In liver biopsies, disorders of the cholangiocytes primary cilium and various degrees of bile duct paucity and dysplasia were identified. In vitro studies combining CNI exposure and siRNA-mediated inhibition of NFATc revealed that calcineurin inhibition decreases HNF1B expression in epithelial cells but independently of NFATc. Conclusions Because HNF1B -related disease is a heterozygous condition, calcineurin inhibitors used to prevent rejection may induce reduced expression of the non-mutated allele of HNF1B leading to a superimposed defect of HNF-1β transcriptional activity. Taking into account the specific risk of PTDM and liver disorders in HNF1B patients, these findings advocate for in-depth characterization of pathways that regulate HNF1B , and plead for considering individually tailored graft management that may include a CNI-free immunosuppressive regimen. Interventional studies will have to confirm this individualized approach.
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calcineurin inhibitors downregulate hnf 1β and may affect the outcome of HNF1B patients after renal transplantation
Transplantation, 2016Co-Authors: Stanislas Faguer, Stephane Decramer, Laure Esposito, Audrey Casemayou, Yves Pirson, Claire Cartery, Marc Hazzan, Valerie Garrigue, Gwenaelle Roussey, Olivier CointaultAbstract:Background Patients with HNF1B mutations develop progressive chronic renal failure, diabetes mellitus (40-50%), and liver tests abnormalities (40-70%). In HNF1B patients who reach end-stage renal disease, single kidney transplantation (SKT) or combined kidney-pancreas transplantation can be considered. Methods A retrospective multicenter study including 18 HNF1B patients receiving SKT or kidney-pancreas transplantation, and in vitro experiments including the characterization of the HNF1B expression after calcineurin inhibitor (CNI) exposure. Results After SKT, 50% of the HNF1B patients develop early posttransplantation diabetes mellitus, whereas 40% experience new-onset or severe worsening of preexisting abnormalities of liver tests, including severe cholestasis. In liver biopsies, disorders of the cholangiocytes primary cilium and various degrees of bile duct paucity and dysplasia were identified. In vitro studies combining CNI exposure and siRNA-mediated inhibition of NFATc revealed that calcineurin inhibition decreases HNF1B expression in epithelial cells but independent of NFATc. Conclusions Because HNF1B-related disease is a heterozygous condition, CNIs used to prevent rejection may induce reduced expression of the nonmutated allele of HNF1B leading to a superimposed defect of HNF-1β transcriptional activity. Taking into account the specific risk of posttransplantation diabetes mellitus and liver disorders in HNF1B patients, these findings advocate for in-depth characterization of pathways that regulate HNF1B and plead for considering individually tailored graft management that may include a CNI-free immunosuppressive regimen. Interventional studies will have to confirm this individualized approach.
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the HNF1B score is a simple tool to select patients for HNF1B gene analysis
Kidney International, 2014Co-Authors: Stanislas Faguer, Flavio Bandin, Audrey Casemayou, Nicolas Chassaing, Cathie Prouheze, Arnaud Garnier, Antoine Huart, Joost P Schanstra, Patrick CalvasAbstract:HNF1B-related disease is an emerging condition characterized by an autosomal-dominant inheritance, a 50% rate of de novo mutations, and a highly variable phenotype (renal involvement, maturity-onset diabetes of the young type 5, pancreatic hypoplasia, and urogenital tract and liver test abnormalities). Given the current lack of pathognomonic characteristics and the wide overlap with other conditions, a genetic test is the diagnostic gold standard. However, pre-genetic screening is mandatory because genetic testing has substantial costs. Our aim was to develop a HNF1B score, based on clinical, imaging, and biological variables, as a pivotal tool for rational genetic testing. A score was created using a weighted combination of the most discriminative characteristics based on the frequency and specificity in published series. The HNF1B score is calculated upon 17 items including antenatal discovery, family history, and organ involvement (kidney, pancreas, liver, and genital tract). The performance of the score was assessed by a ROC curve analysis in a 433-individual cohort containing 56 HNF1B cases. The HNF1B score efficiently and significantly discriminated between mutated and nonmutated cases (AUC 0.78). The optimal cutoff threshold for the negative predictive value to rule out HNF1B mutations in a suspected individual was 8 (sensitivity 98.2%, specificity 41.1%, and negative predictive value over 99%). Thus, the HNF1B score is a simple and accurate tool to provide a more rational approach to select patients for HNF1B screening.
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Expression of Renal Cystic Genes in Patients with HNF1B Mutations.
Nephron. Clinical practice, 2012Co-Authors: Stanislas Faguer, Jeanphilippe Lengele, Stephane Decramer, Olivier Devuyst, Gilbert J. Fournié, Dominique ChauveauAbstract:Background/Aims: HNF1B nephropathy is characterized by dominantly inherited renal hypodysplasia with few cysts, slow renal decline and hypomagnesemia. Mice with antenatal inactivation of HNF1B are characterized by polycystic kidneys, renal failure and a profound decrease in cystic gene (Pkhd1, Umod, Pkd2) expression. Mice with inactivation after postnatal day 10 have no renal phenotype. Methods: Quantification of mRNA expression of HNF1B, six of its potential target genes (PKHD1, PKD1, PKD2, IFT88, TMEM27 and UMOD) and three genes involved in the Mg(2+) renal homeostasis (ATP1A1, FXYD2 and CLDN16) in the urinary sediment of 11 individuals with mutation of HNF1B and in 9 controls (non-invasive assessment of the renal transcriptome). Results: As compared to controls, no difference was observed in the urinary mRNA amount of HNF1B and the renal cystic genes. A significant increase in the expression of ATP1A1, which encodes the α1-subunit of the Na(+)/K(+)-ATPase, was identified in HNF1B patients consistent with its role in Mg(2+) homeostasis. Conclusion:Assessment of mRNA expression in urinary sediment is a non-invasive method applicable to gain insights into the pathophysiology of inherited nephropathies in humans. HNF1B nephropathy is generally not associated with postnatal down-expression of renal cystic genes in human, a finding consistent with mouse models.
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spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases
Clinical Journal of The American Society of Nephrology, 2010Co-Authors: Laurence Heidet, Stephane Decramer, Audrey Pawtowski, Vincent Moriniere, Flavio Bandin, Bertrand Knebelmann, Annesophie Lebre, Stanislas Faguer, Vincent Guigonis, Corinne AntignacAbstract:Background and objectives: Hepatocyte nuclear factor 1β (HNF1β) 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). Results: We found a heterozygous mutation in 75 (19.9%) index cases, consisting of a deletion of the whole gene in 42, deletion of one exon in one, and small mutations in 32. Eighteen mutations were novel. De novo mutations accounted for 66% of deletions and 40% of small mutations. In patients who carried HNF1B mutation and for whom we were able to study prenatal ultrasonography (56 probands), isolated hyperechogenic kidneys with normal or slightly enhanced size were the more frequent (34 of 56) phenotype before birth. Various other prenatal renal phenotypes were associated with HNF1B mutations, at a lesser frequency. Diabetes developed in four probands. Hyperuricemia and hypomagnesemia, although not systematically investigated, were frequently associated. Conclusions: This large series showed that the severity of the renal disease associated with HNF1B mutations was extremely variable (from prenatal renal failure to normal renal function in adulthood) and was not correlated with the genotype.
Stephane Decramer - One of the best experts on this subject based on the ideXlab platform.
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School level of children carrying a HNF1B variant or a deletion
European Journal of Human Genetics, 2020Co-Authors: Fanny Laliève, Brigitte Llanas, Veronique Baudouin, Annie Lahoche, Laurence Heidet, Stephane Decramer, Pierre Cochat, Julie Tenenbaum, Marie-pierre Lavocat, Philippe EckartAbstract:The prevalence of neurological involvement in patients with a deletion of or a variant in the HNF1B gene remains discussed. The aim of this study was to investigate the neuropsychological outcomes in a large cohort of children carrying either a HNF1B whole-gene deletion or a disease-associated variant, revealed by the presence of kidney anomalies. The neuropsychological development—based on school level—of 223 children included in this prospective cohort was studied. Data from 180 children were available for analysis. Patients mean age was 9.6 years, with 39.9% of girls. Among these patients, 119 carried a HNF1B deletion and 61 a disease-associated variant. In the school-aged population, 12.7 and 3.6% of patients carrying a HNF1B deletion and a disease-associated variant had special educational needs, respectively. Therefore, the presence of a HNF1B deletion increases the risk to present with a neuropsychiatric involvement when compared with the general population. On the other hand, almost 90% of patients carrying a HNF1B disease-associated variant or deletion have a normal schooling in a general educational environment. Even if these findings do not predict the risk of neuropsychiatric disease at adulthood, most patients diagnosed secondary to kidney anomalies do not show a neurological outcome severe enough to impede standard schooling at elementary school. These results should be taken into account in prenatal counseling.
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calcineurin inhibitors down regulate hnf 1β and may affect the outcome of HNF1B patients after renal transplantation
Archives De Pediatrie, 2016Co-Authors: Stephane Decramer, Stanislas Faguer, J P SchanstraAbstract:Background Patients with HNF1B mutations develop progressive chronic renal failure, diabetes mellitus (40–50%) and liver tests abnormalities (40–70%). In HNF1B patients who reach end-stage renal disease, single kidney (SKT) or combined kidney-pancreas transplantation (KPT) can be considered. Methods A retrospective multicenter study including 18 HNF1B patients receiving SKT or KPT, and in vitro experiments including the characterization of the HNF1B expression after calcineurin inhibitor (CNI) exposure. Results Following SKT, 50% of the HNF1B patients develop early post-transplantation diabetes mellitus (PTDM), while 40% experience new-onset or severe worsening of pre-existing abnormalities of liver tests, including severe cholestasis. In liver biopsies, disorders of the cholangiocytes primary cilium and various degrees of bile duct paucity and dysplasia were identified. In vitro studies combining CNI exposure and siRNA-mediated inhibition of NFATc revealed that calcineurin inhibition decreases HNF1B expression in epithelial cells but independently of NFATc. Conclusions Because HNF1B -related disease is a heterozygous condition, calcineurin inhibitors used to prevent rejection may induce reduced expression of the non-mutated allele of HNF1B leading to a superimposed defect of HNF-1β transcriptional activity. Taking into account the specific risk of PTDM and liver disorders in HNF1B patients, these findings advocate for in-depth characterization of pathways that regulate HNF1B , and plead for considering individually tailored graft management that may include a CNI-free immunosuppressive regimen. Interventional studies will have to confirm this individualized approach.
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calcineurin inhibitors downregulate hnf 1β and may affect the outcome of HNF1B patients after renal transplantation
Transplantation, 2016Co-Authors: Stanislas Faguer, Stephane Decramer, Laure Esposito, Audrey Casemayou, Yves Pirson, Claire Cartery, Marc Hazzan, Valerie Garrigue, Gwenaelle Roussey, Olivier CointaultAbstract:Background Patients with HNF1B mutations develop progressive chronic renal failure, diabetes mellitus (40-50%), and liver tests abnormalities (40-70%). In HNF1B patients who reach end-stage renal disease, single kidney transplantation (SKT) or combined kidney-pancreas transplantation can be considered. Methods A retrospective multicenter study including 18 HNF1B patients receiving SKT or kidney-pancreas transplantation, and in vitro experiments including the characterization of the HNF1B expression after calcineurin inhibitor (CNI) exposure. Results After SKT, 50% of the HNF1B patients develop early posttransplantation diabetes mellitus, whereas 40% experience new-onset or severe worsening of preexisting abnormalities of liver tests, including severe cholestasis. In liver biopsies, disorders of the cholangiocytes primary cilium and various degrees of bile duct paucity and dysplasia were identified. In vitro studies combining CNI exposure and siRNA-mediated inhibition of NFATc revealed that calcineurin inhibition decreases HNF1B expression in epithelial cells but independent of NFATc. Conclusions Because HNF1B-related disease is a heterozygous condition, CNIs used to prevent rejection may induce reduced expression of the nonmutated allele of HNF1B leading to a superimposed defect of HNF-1β transcriptional activity. Taking into account the specific risk of posttransplantation diabetes mellitus and liver disorders in HNF1B patients, these findings advocate for in-depth characterization of pathways that regulate HNF1B and plead for considering individually tailored graft management that may include a CNI-free immunosuppressive regimen. Interventional studies will have to confirm this individualized approach.
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Expression of Renal Cystic Genes in Patients with HNF1B Mutations.
Nephron. Clinical practice, 2012Co-Authors: Stanislas Faguer, Jeanphilippe Lengele, Stephane Decramer, Olivier Devuyst, Gilbert J. Fournié, Dominique ChauveauAbstract:Background/Aims: HNF1B nephropathy is characterized by dominantly inherited renal hypodysplasia with few cysts, slow renal decline and hypomagnesemia. Mice with antenatal inactivation of HNF1B are characterized by polycystic kidneys, renal failure and a profound decrease in cystic gene (Pkhd1, Umod, Pkd2) expression. Mice with inactivation after postnatal day 10 have no renal phenotype. Methods: Quantification of mRNA expression of HNF1B, six of its potential target genes (PKHD1, PKD1, PKD2, IFT88, TMEM27 and UMOD) and three genes involved in the Mg(2+) renal homeostasis (ATP1A1, FXYD2 and CLDN16) in the urinary sediment of 11 individuals with mutation of HNF1B and in 9 controls (non-invasive assessment of the renal transcriptome). Results: As compared to controls, no difference was observed in the urinary mRNA amount of HNF1B and the renal cystic genes. A significant increase in the expression of ATP1A1, which encodes the α1-subunit of the Na(+)/K(+)-ATPase, was identified in HNF1B patients consistent with its role in Mg(2+) homeostasis. Conclusion:Assessment of mRNA expression in urinary sediment is a non-invasive method applicable to gain insights into the pathophysiology of inherited nephropathies in humans. HNF1B nephropathy is generally not associated with postnatal down-expression of renal cystic genes in human, a finding consistent with mouse models.
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spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases
Clinical Journal of The American Society of Nephrology, 2010Co-Authors: Laurence Heidet, Stephane Decramer, Audrey Pawtowski, Vincent Moriniere, Flavio Bandin, Bertrand Knebelmann, Annesophie Lebre, Stanislas Faguer, Vincent Guigonis, Corinne AntignacAbstract:Background and objectives: Hepatocyte nuclear factor 1β (HNF1β) 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). Results: We found a heterozygous mutation in 75 (19.9%) index cases, consisting of a deletion of the whole gene in 42, deletion of one exon in one, and small mutations in 32. Eighteen mutations were novel. De novo mutations accounted for 66% of deletions and 40% of small mutations. In patients who carried HNF1B mutation and for whom we were able to study prenatal ultrasonography (56 probands), isolated hyperechogenic kidneys with normal or slightly enhanced size were the more frequent (34 of 56) phenotype before birth. Various other prenatal renal phenotypes were associated with HNF1B mutations, at a lesser frequency. Diabetes developed in four probands. Hyperuricemia and hypomagnesemia, although not systematically investigated, were frequently associated. Conclusions: This large series showed that the severity of the renal disease associated with HNF1B mutations was extremely variable (from prenatal renal failure to normal renal function in adulthood) and was not correlated with the genotype.
Andrew T Hattersley - One of the best experts on this subject based on the ideXlab platform.
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genome wide methylomic analysis in individuals with HNF1B intragenic mutation and 17q12 microdeletion
Clinical Epigenetics, 2018Co-Authors: Rhian L Clissold, Andrew T Hattersley, Coralie Bingham, Beth Ashfield, Joe Burrage, Eilis Hannon, Jonathan Mill, Emma DempsterAbstract:Heterozygous mutation of the transcription factor HNF1B is the most common cause of monogenetic developmental renal disease. Disease-associated mutations fall into two categories: HNF1B intragenic mutations and a 1.3 Mb deletion at chromosome 17q12. An increase in neurodevelopmental disorders has been observed in individuals harbouring the 17q12 deletion but not in patients with HNF1B coding mutations. Previous investigations have concentrated on identifying a genetic cause for the increase in behavioural problems seen in 17q12 deletion carriers. We have taken the alternative approach of investigating the DNA methylation profile of these two HNF1B genotype groups along with controls matched for age, gender and diabetes status using the Illumina 450K DNA methylation array (total sample n = 60). We identified a number of differentially methylated probes (DMPs) that were associated with HNF1B-associated disease and passed our stringent experiment-wide significance threshold. These associations were largely driven by the deletion patients and the majority of the significant probes mapped to the 17q12 deletion locus. The observed changes in DNA methylation at this locus were not randomly dispersed and occurred in clusters, suggesting a regulatory mechanism reacting to haploinsufficiency across the entire deleted region. Along with these deletion-specific changes in DNA methylation, we also identified a shared DNA methylation signature in both mutation and deletion patient groups indicating that haploinsufficiency of HNF1B impacts on the methylome of a number of genes, giving further insight to the role of HNF1B.
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HNF1B associated renal and extra renal disease an expanding clinical spectrum
Nature Reviews Nephrology, 2015Co-Authors: Rhian L Clissold, Sian Ellard, Andrew T Hattersley, Alexander J Hamilton, Coralie BinghamAbstract:Heterozygous mutations in the gene that encodes the transcription factor hepatocyte nuclear factor 1β (HNF1B) represent the most common known monogenic cause of developmental kidney disease. Renal cysts are the most frequently detected feature of HNF1B-associated kidney disease; however, other structural abnormalities, including single kidneys and renal hypoplasia, and electrolyte abnormalities can also occur. Extra-renal phenotypes might also be observed; consequently, HNF1B-associated disease is considered a multi-system disorder. Other clinical features include early-onset diabetes mellitus, pancreatic hypoplasia, genital tract malformations, abnormal liver function and early-onset gout. Heterozygous mutations in the coding region or splice sites of HNF1B, and complete gene deletion, each account for ∼50% of all cases of HNF1B-associated disease, respectively, and often arise spontaneously. There is no clear genotype-phenotype correlation, consistent with haploinsufficiency as the disease mechanism. Data from animal models suggest that HNF1B has an important function during several stages of nephrogenesis; however, the precise signalling pathways remain to be elucidated. This Review discusses the genetics and molecular pathways that lead to disease development, summarizes the reported renal and extra-renal phenotypes, and identifies areas for future research in HNF1B-associated disease.
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HNF1B deletions in patients with young onset diabetes but no known renal disease
Diabetic Medicine, 2013Co-Authors: Emma L Edghill, Andrew T Hattersley, Richard A Oram, Maggie Shepherd, Karen Stals, Sian EllardAbstract:Diabet. Med. 30, 114–117 (2013) Abstract Aims Hepatocyte nuclear factor 1β (HNF1B) mutations cause a syndrome of renal cysts and diabetes, with whole gene deletions accounting for approximately 50% of cases. The severity of the renal phenotype is variable, from enlarged cystic kidneys incompatible with life to normal renal development and function. We investigated the prevalence of HNF1B deletions in patients with diabetes but no known renal disease. Methods We tested 461 patients with familial diabetes diagnosed before 45 years, including 258 probands who met clinical criteria for maturity-onset diabetes of the young (two generations affected and at least one family member diagnosed under 25 years). A fluorescent polymerase chain reaction assay was used to analyse two intragenic polymorphic HNF1B markers and identify heterozygous patients who therefore did not have whole gene deletions. Those patients homozygous for both markers were then tested for an HNF1B deletion using multiplex ligation-dependent probe amplification. Results Heterozygous HNF1B intragenic polymorphisms were identified in 337/461 subjects. Multiplex ligation-dependent probe amplification analysis showed an HNF1B gene deletion in three of the remaining 124 probands, all of whom met the criteria for maturity-onset diabetes of the young. Testing of their relatives identified three additional deletion carriers and ultrasound scanning showed renal developmental abnormalities in three of these six patients. Conclusions We estimate that HNF1B mutations account for < 1% of cases of maturity-onset diabetes of the young. Although HNF1B mutations are a rare cause of diabetes in the absence of known renal disease, a genetic diagnosis of renal cysts and diabetes syndrome is important as it raises the possibility of subclinical renal disease and the 50% risk of renal cysts and diabetes syndrome in the patient’s offspring.
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high sensitivity crp discriminates hnf1a mody from other subtypes of diabetes
Diabetes Care, 2011Co-Authors: Timothy J. Mcdonald, Sian Ellard, Beverley M. Shields, Jane Lawry, Katharine R. Owen, Anna L. Gloyn, Andrew T HattersleyAbstract:OBJECTIVE Maturity-onset diabetes of the young (MODY) as a result of mutations in hepatocyte nuclear factor 1-α ( HNF1A ) is often misdiagnosed as type 1 diabetes or type 2 diabetes. Recent work has shown that high-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY than type 1 diabetes, type 2 diabetes, or glucokinase (GCK)-MODY. We aim to replicate these findings in larger numbers and other MODY subtypes. RESEARCH DESIGN AND METHODS hs-CRP levels were assessed in 750 patients (220 HNF1A , 245 GCK , 54 HNF4-α [ HNF4A ], 21 HNF1-β ( HNF1B ), 53 type 1 diabetes, and 157 type 2 diabetes). RESULTS hs-CRP was lower in HNF1A-MODY (median interquartile [IQR] 0.3 [0.1–0.6] mg/L) than type 2 diabetes (median [IQR] 1.40 [0.60–3.45] mg/L; P < 0.001) and type 1 diabetes (median [IQR] 1.10 [0.50–1.85] mg/L; P < 0.001), HNF4A-MODY (median [IQR] 1.45 [0.46–2.88] mg/L; P < 0.001), GCK-MODY (median [IQR] 0.60 [0.30–1.80] mg/L; P < 0.001), and HNF1B-MODY (median [IQR] 0.60 [0.10–2.8] mg/L; P = 0.07). hs-CRP discriminated HNF1A-MODY from type 2 diabetes with hs-CRP <0.75 mg/L showing 79% sensitivity and 70% specificity (receiver operating characteristic area under curve = 0.84). CONCLUSIONS hs-CRP levels are lower in HNF1A-MODY than other forms of diabetes and may be used as a biomarker to select patients for diagnostic HNF1A genetic testing.
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mutations in the hepatocyte nuclear factor 1β HNF1B gene are common with combined uterine and renal malformations but are not found with isolated uterine malformations
American Journal of Obstetrics and Gynecology, 2010Co-Authors: Richard A Oram, Sian Ellard, Emma L Edghill, Jenny Blackman, Miles J O Taylor, Tracey Kay, Sarah E Flanagan, Ida Ismailpratt, Sarah M Creighton, Andrew T HattersleyAbstract:Objective Congenital uterine abnormalities are common and may be associated with developmental renal abnormalities. Mutations of the hepatocyte nuclear factor-1β ( HNF1B) gene are associated with renal and uterine abnormalities. We aimed to study the role of HNF1B mutations in a cohort with congenital uterine abnormalities. Study Design We tested 108 probands with uterine abnormalities for HNF1B mutations. We collected clinical information from patient records. Results Nine of 108 women (8%) had a mutation or deletion in the HNF1B gene. Abnormal HNF1B was found in 18% of the 50 probands who had both uterine and renal abnormalities but in none of the 58 women with isolated uterine abnormalities. Conclusion Mutations of the HNF1B gene are found in women with both uterine and renal abnormalities but are rare in isolated uterine abnormalities. We suggest that HNF1B testing should be performed in patients with both renal and uterine abnormalities, but not in patients with isolated uterine abnormalities.
Jianqing Wang - One of the best experts on this subject based on the ideXlab platform.
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HNF1B inhibits cell proliferation via repression of smad6 expression in prostate cancer
Journal of Cellular and Molecular Medicine, 2020Co-Authors: Jian Sun, Huihui Zhou, Fei Wang, Chunchun Zhao, Caibin Fan, Guanxiong Ding, Jianqing WangAbstract:Prostate cancer is the most common malignancy in men in developed countries. In previous study, we identified HNF1B (Hepatocyte Nuclear Factor 1β) as a downstream effector of Enhancer of zeste homolog 2 (EZH2). HNF1B suppresses EZH2-mediated migration of two prostate cancer cell lines via represses the EMT process by inhibiting SLUG expression. Besides, HNF1B expression inhibits cell proliferation through unknown mechanisms. Here, we demonstrated that HNF1B inhibited the proliferation rate of prostate cancer cells. Overexpression of HNF1B in prostate cancer cells led to the arrest of G1 cell cycle and decreased Cyclin D1 expression. In addition, we re-explored data from ChIP-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq), and demonstrated that HNF1B repressed Cyclin D1 via direct suppression of SMAD6 expression. We also identified CDKN2A as a HNF1B-interacting protein that would contribute to HNF1B-mediated repression of SMAD6 expression. In summary, we provide the novel mechanisms and evidence in support HNF1B as a tumour suppressor gene for prostate cancer.
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HNF1B mediated repression of slug is suppressed by ezh2 in aggressive prostate cancer
Oncogene, 2020Co-Authors: Jianqing Wang, Jian Sun, Huihui Zhou, Caibin Fan, Guanxiong Ding, Peng Gao, Siqing Wang, Qidong Zhou, Ke Zhang, Fei LanAbstract:Prostate cancer is the most common malignancy in men in developed countries. Overexpression of enhancer of zeste homolog 2 (EZH2), the major histone H3 lysine 27 methyltransferase, has been connected to prostate cancer malignancy. However, its downstream genes and pathways have not been well established. Here, we show tumor suppressor Hepatocyte Nuclear Factor 1β (HNF1B) as a direct downstream target of EZH2. EZH2 binds HNF1B locus and suppresses HNF1B expression in prostate cancer cell lines, which is further supported by the reverse correlation between EZH2 and HNF1B expression in clinical samples. Consistently, restored HNF1B expression significantly suppresses EZH2-mediated overgrowth and EMT processes, including migration and invasion of prostate cancer cell lines. Mechanistically, we find that HNF1B primarily binds the promoters of thousands of target genes, and differentially regulates the expression of 876 genes. We also identify RBBP7/RbAP46 as a HNF1B interacting protein which is required for HNF1B-mediated repression of SLUG expression and EMT process. Importantly, we find that higher HNF1B expression strongly predicts better prognosis of prostate cancer, alone or together with lower EZH2 expression. Taken together, we have established a previously underappreciated axis of EZH2-HNF1B-SLUG in prostate cancer, and also provide evidence supporting HNF1B as a potential prognosis marker for metastatic prostate cancer.