HNF-1beta Mutations Research Articles

Pregnancy outcome with maternal HNF1B gene mutations and 17q12 deletions.

There is an increasing body of literature regarding monogenic diabetes, particularly the more common forms of glucokinase and HNF1-alpha mutations (MODY2 and MODY3). There is relatively little published literature regarding rarer mutations. HNF1-beta mutations and 17q12 deletions may be associated with a broad range of organ dysfunction, renal disease and diabetes in particular resulting in high-risk pregnancies. This manuscript describes pregnancy outcomes in a woman with an HNF1-beta mutation and 2 women with an HNF1B/17q12 deletion and reviews the previously published literature. It highlights the significant rate of adverse maternal and fetal outcomes, and the maternal features suggestive of the diagnosis which should be considered in preconception counselling.

A Rare Cause of Polyuria and Polydipsia in a Patient With Cystic Renal Disease: Maturity-Onset Diabetes of the Young Type 5

Hepatocyte nuclear factor-1beta (HNF-1beta) is a transcription factor that is responsible for the development of kidney, pancreas, liver and genitourinary tract. Affected individuals may present a variety of renal developmental abnormalities and/or maturity-onset diabetes of the young type 5 (MODY 5). Here we report a boy with autosomal recessive polycystic kidney disease (ARPKD) diagnosed in neonatal period who developed insulin-dependent diabetes at the age of 11. He presented with poliuria and polydipsia. The diagnosis of ARPKD was made in neonatal period based on the findings of large hyperechogenic kidneys in antenatal ultrasound and no history of renal disease in parents. Laboratory investigations revealed hyperglycemia, glycosuria, and a reduced glomerular filtration rate (GFR). Based on autoantibody-negative diabetes and low-dose insulin requirement in addition to renal anomalies, he was suspected to have MODY 5. Genetic studies identified a known heterozygous HNF1B gene mutation (S148L) compatible with an MODY 5 phenotype. As a result, MODY 5 should be considered in children with developmental kidney disease and hyperglycemia. Also HNF-1beta mutations should be suspected in patients with undefined cystic kidney disease especially when associated with other systemic findings as in our case. World J Nephrol Urol. 2016;5(3):67-70 doi: http://dx.doi.org/10.14740/wjnu272w

HNF-1beta mutation affects PKD2 and SOCS3 expression causing renal cysts and diabetes in MODY5 kindred

Maturity onset diabetes of young (MODY) type 5 is a form of non-insulin-dependent diabetes mellitus associated with renal cysts. It is an autosomal dominant disorder caused by mutations in the gene encoding hepatocyte nuclear factor-1β (HNF-1β). We performed molecular screening of HNF-1β in a 13-year-old patient and his affected father, and analyzed polycystic kidney disease 2 (PKD2) gene and suppressor of cytokine signaling 3 (SOCS3) expression in lymphoblastoid cell lines and lymphocytes from both patients. We found a novel HNF-1β frameshift mutation (c.C1304del) that results in a truncated protein (p.I434IfsX1). The genetic change is localized in the transactivated protein domain. We demonstrated that this novel HNF-1β mutation strongly influences the expression of both PKD2, responsible for the formation of the renal cysts, and SOCS3, which is associated with early diabetes onset.

Clinical implications of a molecular genetic classification of monogenic β-cell diabetes

Monogenic diabetes resulting from mutations that primarily reduce beta-cell function accounts for 1-2% of diabetes cases, although it is often misdiagnosed as either type 1 or type 2 diabetes. Knowledge of the genetic etiology of diabetes enables more-appropriate treatment, better prediction of disease progression, screening of family members and genetic counseling. We propose that the old clinical classifications of maturity-onset diabetes of the young and neonatal diabetes are obsolete and that specific genetic etiologies should be sought in four broad clinical situations because of their specific treatment implications. Firstly, diabetes diagnosed before 6 months of age frequently results from mutation of genes that encode Kir6.2 (ATP-sensitive inward rectifier potassium channel) or sulfonylurea receptor 1 subunits of an ATP-sensitive potassium channel, and improved glycemic control can be achieved by treatment with high-dose sulfonylureas rather than insulin. Secondly, patients with stable, mild fasting hyperglycemia detected particularly when they are young could have a glucokinase mutation and might not require specific treatment. Thirdly, individuals with familial, young-onset diabetes that does not fit with either type 1 or type 2 diabetes might have mutations in the transcription factors HNF-1alpha (hepatocyte nuclear factor 1-alpha) or HNF-4alpha, and can be treated with low-dose sulfonylureas. Finally, extrapancreatic features, such as renal disease (caused by mutations in HNF-1beta) or deafness (caused by a mitochondrial m.3243A>G mutation), usually require early treatment with insulin.

Hepatocyte nuclear factor-1 gene deletions--a common cause of renal disease

Hepatocyte nuclear factor-1beta (HNF-1beta) is a critical transcription factor in pancreatic and renal development. Our previous report identified HNF-1beta mutations in 23/160 patients with unexplained renal disease. The most common phenotype is renal cysts, which is frequently associated with early-onset diabetes in the renal cysts and diabetes (RCAD) syndrome. HNF-1beta gene deletions have recently been shown to cause renal malformations and early-onset diabetes. We developed a multiplex ligation-dependent probe amplification (MLPA) assay for HNF-1beta gene dosage analysis and tested patients with unexplained renal disease in whom mutations had not been found by sequencing. Whole HNF-1beta gene deletions were detected in 15/133 probands. Renal cysts were present in 13/15, including three with glomerulocystic kidney disease and one with cystic renal dysplasia. Renal function ranged from normal to transplantation aged 3 years. Ten probands had diabetes (nine having RCAD). In addition, four had abnormal liver function tests, two showed pancreatic atrophy and 3/10 female probands had uterine malformations. Whole HNF-1beta gene deletions are a common cause of developmental renal disease, particularly renal cystic disease with or without diabetes. The phenotype associated with deletions or coding region/splicing mutations is very similar suggesting that haploinsufficiency is the underlying mechanism. Patients with features suggestive of the HNF-1beta clinical phenotype should be tested for mutations both by sequence and dosage analysis.

Mutations in BHD and TP53 genes, but not in HNF1β gene, in a large series of sporadic chromophobe renal cell carcinoma

BHD, TP53, and HNF1β 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 HNF1β mutations, (84% mutations involved chromophobe), suggesting a role for BHD and TP53 in chromophobe subtype.

Hepatocyte nuclear factor‐1 beta mutations cause neonatal diabetes and intrauterine growth retardation: support for a critical role of HNF‐1β in human pancreatic development

The transcription factor hepatocyte nuclear factor-1beta (HNF-1beta) is expressed in rodent pancreatic progenitor cells, where it is an important member of the genetic hierarchy that regulates the generation of pancreatic endocrine and exocrine cells. The recent description of an HNF-1beta mutation in a patient with neonatal diabetes suggests that HNF-1beta may also play a key role in human pancreatic B-cell development. We aimed to investigate the role of HNF-1beta mutations in neonatal diabetes and also the impact of HNF-1beta mutations on fetal growth. We sequenced the HNF-1beta gene in 27 patients with neonatal diabetes in whom other known genetic aetiologies had been excluded. Birth weight was investigated in 21 patients with HNF-1beta mutations. A heterozygous HNF-1beta mutation, S148L, was identified in one patient with neonatal diabetes diagnosed at 17 days, which rapidly resolved only to relapse at 8 years. This patient had pancreatic atrophy, mild exocrine insufficiency and low birth weight (1.83 kg at 40 weeks' gestation). Intrauterine growth was markedly reduced in patients born to unaffected mothers with a median birth weight of 2.4 kg (range 1.8-3.3) (P = 0.006), median centile weight 3 (0.008-38), and 69% were small for gestational age. HNF-1beta mutations are a rare cause of neonatal diabetes as well as pancreatic exocrine and endocrine dysfunction. Low birth weight is a common feature of patients with HNF-1beta mutations and is consistent with reduced insulin secretion in utero. These findings support a key role for HNF-1beta in early pancreatic progenitor cells in man.

Minireview: Pharmacogenetics and Beyond: The Interaction of Therapeutic Response, β-Cell Physiology, and Genetics in Diabetes

Defining the molecular genetics of diabetes gives new insight into the underlying etiology and so should help improve treatment. The genetic etiology is now known for most patients with beta-cell monogenic diabetes, allowing genetic classification. We review how this genetic knowledge alters treatment. Patients with a glucose-sensing beta-cell defect due to glucokinase mutations have regulated, mild, fasting hyperglycemia. Oral hypoglycemic agents or low-dose insulin rarely improve glycemic control. Patients with hepatic nuclear factor-1alpha (HNF1alpha) mutations have progressive beta-cell deterioration and require treatment. HNF1alpha patients are 4 times more sensitive to sulfonylureas than matched type 2 diabetic patients. This is partly due to greater insulin secretion, reflecting the fact that the defect in HNF1alpha deficiency precedes the K(ATP) channel where sulfonylureas act. HNF1beta is expressed in pancreatic stem cells before differentiation into endocrine or exocrine cells, so patients with HNF1beta mutations have reduced pancreatic development, resulting in early-onset diabetes and exocrine dysfunction. These patients usually rapidly require insulin and are not sensitive to sulfonylureas. Thirty-five to 50% of patients diagnosed with diabetes before 6 months have a mutation in Kir6.2. The mutated KATP channel in these patients does not close in response to increased ATP concentrations, but can be closed when sulfonylureas bind to the sulfonylurea receptor 1 subunit of the channel by an ATP-independent route. These patients are usually insulin dependent, but have excellent glycemic control on high-dose sulfonylureas tablets. In conclusion, the defining of molecular genetic etiology in monogenic diabetes has identified several specific beta-cell defects, and these are critical in determining the response to treatment.

The position of premature termination codons in the hepatocyte nuclear factor −1 beta gene determines susceptibility to nonsense-mediated decay

The nonsense-mediated decay (NMD) pathway is an mRNA surveillance mechanism that detects and degrades transcripts containing premature termination codons. The position of a truncating mutation can govern the resulting phenotype as mutations in the last exon evade NMD. In this study we investigated the susceptibility to NMD of six truncating HNF-1beta mutations by allele-specific quantitative real-time PCR using transformed lymphoblastoid cell lines. Four of six mutations (R181X, Q243fsdelC, P328L329fsdelCCTCT and A373fsdel29) showed evidence of NMD with levels of mutant transcript at 71% (p=0.009), 24% (p=0.008), 22% (p=0.008) and 3% (p=0.016) of the wild-type allele respectively. Comparable results were derived from lymphoblastoid cells and renal tubule cells isolated from a patient's overnight urine confirming that cell lines provide a good model for mRNA analysis. Two mutations (H69fsdelAC and P159fsdelT) produced transcripts unexpectedly immune to NMD. We conclude that truncating mutant transcripts of the HNF-1beta gene do not conform to the known rules governing NMD susceptibility, but instead demonstrate a previously unreported 5' to 3' polarity. We hypothesise that this may be due to reinitiation of translation downstream of the premature termination codon. Our study suggests that reinitiation of translation may be an important mechanism in the evasion of NMD, but that other factors such as the distance from the native initiation codon may also play a part.

Scanning for MODY5 gene mutations in Chinese early onset or multiple affected diabetes pedigrees

Mutation of HNF-1beta gene has been reported in early onset diabetes or MODY families and this gene has been defined as MODY5 gene. The aim of our study was to examine whether HNF-1beta mutation contribute to early onset or multiple affected diabetes pedigrees in Chinese. Molecular scanning of HNF-1beta gene promoter region, nine exons and flanking introns was performed in 154 unrelated probands from early onset and multiple affected diabetes Chinese pedigrees. The family members of probands with mutations or variants and 58 nondiabetics were also examined. Clinical examinations of renal morphology, renal function and beta-cell function were performed in the HNF-1beta gene mutation carriers and family members. Mutation of HNF-1beta gene causing the substitution S36F was found in two subjects of an early onset diabetic family. One carrier has early onset diabetes, renal function impairment and renal cyst, while the other has impaired glucose tolerance only. This is the first case of MODY5 gene mutation diabetes found in the Chinese. Three HNF-1beta variants were identified and no significant differences in allele frequencies for these variants were detected between the nondiabetic and diabetic groups. Nucleotide 66 of intron 8 of HNF-1beta gene was G in the Chinese population rather than A as noted in the GenBank sequence. These results suggest that HNF-1beta gene mutations may be associated with nondiabetic renal dysfunction and diabetes in Chinese, but they are responsible for only a small percentage of early onset or multiple affected diabetes pedigrees including MODY.

The HNF1beta transcription factor has several domains involved in nephrogenesis and partially rescues Pax8/lim1-induced kidney malformations.

The tissue-specific transcription factors HNF1alpha and HNF1beta are closely related homeodomain proteins conserved in vertebrate evolution. Heterozygous mutations in human HNF1beta but not in HNF1alpha genes are associated with kidney malformations. Overexpression of HNF1beta in Xenopus embryos leads to defective pronephros development, while HNF1alpha has no effect. We have defined the regions responsible for this functional difference between HNF1beta and HNF1alpha in transfected HeLa cells as well as in injected Xenopus embryos. Using domain swapping experiments, we located a nuclear localization signal in the POUH domain of HNF1beta, and showed that the POUS and POUH domains of HNF1beta mediate a high transactivation potential in transfected cells. In injected Xenopus embryos three HNF1beta domains are involved in nephrogenesis. These include the dimerization domain, the 26 amino acid segment specific for splice variant A as well as the POUH domain. As HNF1beta together with Pax8 and lim1 constitute the earliest regulators in the pronephric anlage, it is possible that they cooperate during early nephrogenesis. We have shown here that HNF1beta can overcome the enlargement and the induction of an ectopic pronephros mediated by overexpression of Pax8 and lim1. However, the phenotype induced by Pax8 and lim1 overexpression and characterized by cyst-like structures and thickening of the pronephric tubules was not altered by HNF1beta overexpression. Taken together, HNF1beta acts antagonistically to Pax8 and lim1 in only some processes during nephrogenesis, and a simple antagonistic relationship does not completely describe the functions of these genes. We conclude that HNF1beta has some distinct morphogenetic properties during nephrogenesis.

Selective deletion of the Hnf1beta (MODY5) gene in beta-cells leads to altered gene expression and defective insulin release.

Hepatocyte nuclear factor 1alpha (HNF1alpha) and HNF1beta (or vHNF1) are closely related transcription factors expressed in liver, kidney, gut, and pancreatic beta-cells. Many HNF1 target genes are involved in carbohydrate metabolism. Human mutations in HNF1alpha or HNF1beta lead to maturity-onset diabetes of the young (MODY3 and MODY5, respectively), and patients present with impaired glucose-stimulated insulin secretion. The underlying defect in MODY5 is not known. Analysis of HNF1beta deficiency in mice has not been possible because HNF1beta null mice die in utero. To examine the role of HNF1beta in glucose homeostasis, viable mice deleted for HNF1beta selectively in beta-cells (beta/H1beta-KO mice) were generated using a Cre-LoxP strategy. beta/H1beta-KO mice had normal growth, fertility, fed or fasted plasma glucose and insulin levels, pancreatic insulin content, and insulin sensitivity. However, beta/H1beta-KO mice exhibited impaired glucose tolerance with reduced insulin secretion compared with wild-type mice but preserved a normal insulin secretory response to arginine. Moreover, beta/H1beta-KO islets had increased HNF1alpha and Pdx-1, decreased HNF4 mRNA levels, and reduced glucose-stimulated insulin release. These results indicate that HNF1beta is involved in regulating the beta-cell transcription factor network and is necessary for glucose sensing or glycolytic signaling.

Abnormal splicing of hepatocyte nuclear factor-1 beta in the renal cysts and diabetes syndrome.

Mutations in the hepatocyte nuclear factor-1 beta ( HNF-1 beta) gene result in disorders of renal development, typically involving renal cysts and early-onset diabetes (the RCAD syndrome/ MODY5). Sixteen mutations have been reported, including three splicing mutations of the intron 2 splice donor site. Because tissues showing abundant expression (kidney, liver, pancreas, gut, lung and gonads) are not easily accessible for analysis in living subjects, it has previously proven difficult to determine the effect of HNF-1 beta mutations at the mRNA level. This is the aim of the present study. We have developed a nested RT-PCR assay that exploits the presence of ectopic HNF-1 beta transcripts in Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines derived from subjects carrying HNF-1 beta splice site mutations. We report a fourth mutation of the intron 2 splice donor site, IVS2nt+2insT. Sequence analysis of ectopic HNF-1 beta transcripts showed that both IVS2nt+2insT and IVS2nt+1G>T result in the deletion of exon 2 and are predicted to result in premature termination of the HNF-1 beta protein. Mutant transcripts were less abundant than the normal transcripts but there was no evidence of nonsense-mediated decay. This is the first study to define the pathogenic consequences of mutations within the HNF-1 beta gene by mRNA analysis. This type of approach is a useful and important tool to define mutational mechanisms and determine pathogenicity.

A transcriptional network in polycystic kidney disease

Mutations in cystic kidney disease genes represent a major genetic cause of end-stage renal disease. However, the molecular cascades controlling the expression of these genes are still poorly understood. Hepatocyte Nuclear Factor 1beta (HNF1beta) is a homeoprotein predominantly expressed in renal, pancreatic and hepatic epithelia. We report here that mice with renal-specific inactivation of HNF1beta develop polycystic kidney disease. We show that renal cyst formation is accompanied by a drastic defect in the transcriptional activation of Umod, Pkhd1 and Pkd2 genes, whose mutations are responsible for distinct cystic kidney syndromes. In vivo chromatin immunoprecipitation experiments demonstrated that HNF1beta binds to several DNA elements in murine Umod, Pkhd1, Pkd2 and Tg737/Polaris genomic sequences. Our results uncover a direct transcriptional hierarchy between HNF1beta and cystic disease genes. Interestingly, most of the identified HNF1beta target gene products colocalize to the primary cilium, a crucial organelle that plays an important role in controlling the proliferation of tubular cells. This may explain the increased proliferation of cystic cells in MODY5 patients carrying autosomal dominant mutations in HNF1beta.

Enlarged nephrons and severe nondiabetic nephropathy in hepatocyte nuclear factor-1β (HNF-1β) mutation carriers

Mutations in hepatocyte nuclear factor-1beta (HNF-1beta) lead to a syndrome with diabetes and urogenital malformations [maturity onset of diabetes of the young, type 5 (MODY5)]. The aim of this study was to perform a clinicopathologic investigation of the renal disease in members of a Norwegian family with the HNF-1beta mutation R137-K161del. The study was based on long-term clinical observations of five mutation carriers, combined with renal biopsies from four of these. The biopsies were examined by light microscopy, immunohistochemistry, and transmission electron microscopy. The diameter of the glomerulus, proximal and distal tubules, in addition to thickness of the glomerular basement membrane (GBM), were measured in light microscopic slides and transmission electron micrographs. The results were compared with biopsies from adult patients with diabetic glomerulopathy, glomerulonephritis, and/or benign nephrosclerosis, and children with minimal-change glomerulopathy or glomerulonephritis, respectively. Clinically, there was a wide intrafamilial variation from stable or slightly increasing serum creatinine to progressive renal failure and end-stage renal disease (ESRD). In all cases, the kidney disease was diagnosed prior to diabetes. Hypertrophy of the proximal and distal tubules as well as enlarged glomeruli were found in three of four mutation carriers. Essentially normal nephrons were found in the 10-year-old boy. The thickness of the GBM was considered near normal in all mutation carriers. Oligomeganephronia was found in one patient. Histopathologic and morphometric studies of kidney biopsies from four carriers of an HNF-1beta mutation revealed enlarged glomeruli and tubular structures. Long-term clinical follow-up demonstrated that the renal disease developed prior to and independently of diabetes. Finally, there is a wide phenotypic variation of the renal disease caused by HNF-1beta mutations.

Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1β gene mutation

Familial juvenile hyperuricemic nephropathy (FJHN) is a dominantly inherited condition characterized by young-onset hyperuricemia, gout, and renal disease. The etiologic genes are unknown, although a locus on chromosome 16 has been identified in some kindreds. Mutations in the gene encoding hepatocyte nuclear factor (HNF)-1beta have been associated with dominant inheritance of a variety of disorders of renal development, particularly renal cystic disease and early onset diabetes; hyperuricemia has been reported in some kindreds. To assess a possible role for the HNF-1beta gene in some FJHN kindreds we sequenced the HNF-1beta gene in subjects from three unrelated FJHN families with atypical features of renal cysts or abnormalities of renal development. We also compared serum urate levels in subjects with HNF-1beta mutations with populations of controls, type 2 diabetic subjects, and subjects with mild chronic renal failure without HNF-1beta mutations. A splice-site mutation in intron 2, designated IVS2+1G>T, showed complete co-segregation with FJHN in one family with diabetes. Serum urate levels were significantly higher in the HNF-1beta subjects compared with the normal control subjects (384 micromol/L vs. 264 micromol/L, P = 0.002) and the type 2 diabetic subjects (397 micromol/L vs. 271 micromol/L, P = 0.01). Comparison of serum urate levels in the HNF-1beta subjects with gender-matched subjects with renal impairment of other causes did not reach significance (402 micromol/L vs. 352 micromol/L, P = 0.2). Hyperuricemia and young-onset gout are consistent features of the phenotype associated with HNF-1beta mutations, but the mechanism is uncertain. Families with HNF-1beta mutations may fit diagnostic criteria for FJHN. Identification of HNF-1beta patients by recognizing the features of diabetes and disorders of renal development is important in resolving the genetic heterogeneity in FJHN.

Solitary functioning kidney and diverse genital tract malformations associated with hepatocyte nuclear factor-1β mutations

Renal tract malformations are, on occasion, associated with uterine malformations. The transcription factor hepatocyte nuclear factor (HNF)-1beta is expressed from the earliest stages of development of the Wolffian duct, the mesonephros and metanephros, and the Müllerian ducts in the mouse. In adult mice HNF-1beta is expressed in the kidney tubules, collecting ducts, and in the oviducts and uterus in the female (Müllerian duct derivatives) and in the epididymis, vas deferens and seminal vesicles (Wolffian duct derivatives) in the male. HNF-1beta mutations have been reported in two families where affected members have renal abnormalities, female genital tract malformations and early-onset diabetes. Renal and uterine abnormalities have not been described in families without early-onset diabetes. We sequenced the HNF-1beta gene in nine subjects with renal abnormalities and a personal or family history of female genital tract malformations, but no history of diabetes. Two families were identified with novel HNF-1beta mutations: a missense mutation in exon 2 with conversion of serine to proline at codon 151 (S151P) and a frameshift mutation in exon 3 with a 1 base pair deletion at codon 243 (Q243fsdelC). The S151P mutation proband has cystic kidneys and uterus didelphys. Her affected second son has renal cysts and hypospadias. The Q243fsdelC proband has a single functioning kidney and her two children have renal dysplasia. Histology in one child shows cystic dysplasia with a lack of glomeruli. The proband's sister is a mutation carrier and has a bicornuate uterus. Diabetes is not a feature in either family. This study confirms an association between HNF-1beta mutations and renal and Müllerian anomalies. The hypospadias may be coincidental. This study describes the first HNF-1beta mutations that are associated with a single functioning kidney and the absence of diabetes. This study further reinforces the variability of the renal and non-renal phenotypes associated with HNF-1beta mutations.

Studies of the variability of the hepatocyte nuclear factor-1beta (HNF-1beta / TCF2) and the dimerization cofactor of HNF-1 (DcoH / PCBD) genes in relation to type 2 diabetes mellitus and beta-cell function.

Mutations in the homeodomain-containing transcription factor hepatocyte nuclear factor-1beta (HNF-1beta) are known to cause a rare subtype of maturity-onset diabetes of the young (MODY5), which is associated with early-onset progressive non-diabetic renal dysfunction. To investigate whether mutations in HNF-1 are implicated in the pathogenesis of MODY or late-onset diabetes with and without nephropathy in Danish Caucasians we examined the HNF-1beta (TCF2) and the dimerization cofactor of HNF-1 (DCoH, PCBD) genes for mutations in 11 MODY probands, 28 type 2 diabetic patients with nephropathy, and 46 type 2 diabetic patients with an impaired beta-cell function by combined single-strand conformation polymorphism (SSCP) and heteroduplex analysis. Analysis of the promoter and nine exons including intron-exon boundaries of the HNF-1beta gene revealed one novel silent polymorphism and three previously reported intronic variants. The silent polymorphism (I91I) was found in one patient with late-onset type 2 diabetes. One of the intronic variant (IVS6+26T-->C) was examined further. Among 584 type 2 diabetic patients the allelic frequency was 13.1% (11.2-15.0%) compared to 11.6% (8.6-14.5%) in 229 glucose tolerant control subjects (NS). No difference in insulin secretion during an OGTT was seen between carriers of the different IVS6+26T-->C genotypes among the 229 middle-aged control subjects, nor among 302 glucose tolerant 60-year-old Danish Caucasians. Mutation analysis of the four exons comprising the DCoH gene revealed a previously described A-->G polymorphism located in the 3' untranslated region, which was not investigated further. In conclusion, mutations in HNF-1beta and DCoH are not a major cause of MODY or late onset type 2 diabetes in Danish Caucasian subjects.

Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization.

Maturity-onset diabetes of the young is a heterogeneous group of autosomal dominantly inherited, young-onset beta-cell disorders. At least two consecutive generations are affected with a family member diagnosed before 25 years of age. Diabetes is caused either by mutations in the glucokinase gene (glucokinase MODY) or by mutations in transcription factors (transcription factor MODY). Glucokinase maturity-onset diabetes of the young is a mild, non-progressive hyperglycaemia caused by a resetting of the pancreatic glucose sensor. It is treated with diet, and complications are rare. Pregnancies affected by glucokinase mutations have specific management strategies and prognosis. Transcription factor maturity-onset diabetes of the young, caused by mutations in the hepatocyte nuclear factor genes HNF-1alpha, HNF-4alpha and HNF-1beta, and in insulin promoter factor-1 results in a progressive beta-cell defect with increasing treatment requirements and diabetic complications. Cystic renal disease is a prominent feature of HNF-1beta mutations. Further maturity-onset diabetes of the young genes remain to be identified. MODY is part of the differential diagnosis of diabetes presenting in the first to third decades of life. Diagnostic molecular genetic testing is available for the more common genes involved.

Beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors.

beta-Cell transcription factor genes are important in the pathophysiology of the beta-cell, with mutations in hepatocyte nuclear factor (HNF)-1alpha, HNF-4alpha, insulin promoter factor (IPF)-1, HNF-1beta, and NeuroD1/BETA2, all resulting in early-onset type 2 diabetes. We assessed the relative contribution of these genes to early-onset type 2 diabetes using linkage and sequencing analysis in a cohort of 101 families (95% U.K. Caucasian). The relative distribution of the 90 families fitting maturity-onset diabetes of the young (MODY) criteria was 63% HNF-1alpha, 2% HNF-4alpha, 0% IPF-1, 1% HNF-1beta, 0% NeuroD1/ BETA2, and 20% glucokinase. We report the molecular genetic and clinical characteristics of these patients including 29 new families and 8 novel HNF-1alpha gene mutations. Mutations in the transactivation domain are more likely to be protein truncating rather than result in amino acid substitutions, suggesting that a relatively severe disruption of this domain is necessary to result in diabetes. Mutations in the different transcription factors result in clinical heterogeneity. IPF-1 mutations are associated with a higher age at diagnosis (42.7 years) than HNF-1alpha (20.4 years), HNF-1beta (24.2 years), or HNF-4alpha (26.3 years) gene mutations. Subjects with HNF-1beta mutations, in contrast to the other transcription factors, frequently present with renal disease. A comparison of age at diagnosis between subjects with different types and locations of HNF-1alpha mutations did not reveal genotype-phenotype correlations. In conclusion, mutations in transcription factors expressed in the beta-cell are the major cause of MODY, and the phenotype clearly varies with the gene that is mutated. There is little evidence to indicate that different mutations within the same gene have different phenotypes.