HNF1A Mutations Research Articles

Dipeptidyl Peptidase-IV Inhibitors Are Efficient Adjunct Therapy in HNF1A Maturity-Onset Diabetes of the Young Patients—Report of Two Cases

In HNF1A maturity-onset diabetes of the young (MODY), sulfonylurea (SU) is the first-line treatment. Over time, such therapy fails, and additional treatment is required. Dipeptidyl peptidase IV (DPP-IV) inhibitors are new agents that lower blood glucose by prolonging the activity of circulating incretins. We applied DPP-IV inhibitors in two HNF1A MODY patients whose earlier therapeutic regimen included SU. Case 1, a 39-year-old woman, a carrier of the ArgR171X HNF1A mutation, with a 7-year history of diabetes was on 160 mg of gliclazide and 2,000 mg of metformin. Her initial hemoglobin A1c (HbA1c) level was 7.2%, while the mean glucose level on the CGMS((R)) (Medtronic, Northridge, CA) record was 162 mg/dL. Sitagliptine, in a dose of 100 mg/day, was added to the previous treatment. Case 2, a 62-year-old woman, a carrier of the IVS7nt-6G>A mutation, with a 41-year history of diabetes was treated with 240 mg/day gliclazide and 6 IU of insulin/day. Her initial HbA1c was 8.8%, and average glycemia reached 172 mg/dL. In her case, we started the combined therapy with 50 mg of vildagliptine twice daily. Patients were reexamined after 3 months, and HbA1c fell to 6.3% in both subjects. Similarly, significant improvement in glycemic control on CGMS was observed as the average glycemia decreased to 114 mg/dL and 134 mg/dL in Case 1 and Case 2, respectively. No episodes of hypoglycemia or other side effects were recorded. As intravenous glucose tolerance tests (IVGTTs) were performed before and after DPP-IV implementation, we were able to assess their impact on insulin secretion under fasting conditions. We saw a substantial rise in insulin level increment during IVGTT (by 9.8 and13.4 mIU/L in Case 1 and Case 2, respectively). DPP-IV inhibitors may be an effective tool of combined therapy in HNF1A MODY, and they seem to improve beta-cell function under fasting conditions.

Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations.

ObjectiveThe phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH).Subjects and methodsWe sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype.ResultsA genetic diagnosis was possible for 59/220 (27%) patients. KATP channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years.ConclusionsIn this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once KATP channel mutations have been excluded.

Increased all-cause and cardiovascular mortality in monogenic diabetes as a result of mutations in the HNF1A gene.

To investigate all-cause and cardiovascular mortality in subjects with diabetes caused by a mutation in the hepatocyte nuclear factor 1alpha gene (HNF1A). We identified 39 British families with HNF1A mutations. Consenting individuals were asked details of age and cause of death of parents and siblings. Copies of death certificates were requested from the family or were obtained via the Offices for National Statistics. Data were collated on 241 control subjects and 153 mutation carriers. Of those who died, 66% of mutation carriers died from a cardiovascular-related illness compared with 43% of control subjects (P = 0.02). Family members with HNF1A mutations died at a younger age than familial control subjects [all-cause hazard ratio, adjusting for sex and smoking status: 1.9 (95% confidence interval 1.2, 2.9, P = 0.006; cardiovascular hazard ratio: 2.3, confidence interval 1.3, 4.2, P = 0.006)]. We have shown that individuals known to have diabetes caused by a mutation in the HNF1A gene have an increased risk of cardiovascular mortality compared with their unaffected family members. As with other forms of diabetes, consideration should be given to early statin therapy despite a seemingly protective lipid profile.

Evaluation of Serum 1,5 Anhydroglucitol Levels as a Clinical Test to Differentiate Subtypes of Diabetes

OBJECTIVEAssignment of the correct molecular diagnosis in diabetes is necessary for informed decisions regarding treatment and prognosis. Better clinical markers would facilitate discrimination and prioritization for genetic testing between diabetes subtypes. Serum 1,5 anhydroglucitol (1,5AG) levels were reported to differentiate maturity-onset diabetes of the young due to HNF1A mutations (HNF1A-MODY) from type 2 diabetes, but this requires further validation. We evaluated serum 1,5AG in a range of diabetes subtypes as an adjunct for defining diabetes etiology.RESEARCH DESIGN AND METHODS1,5AG was measured in U.K. subjects with: HNF1A-MODY (n = 23), MODY due to glucokinase mutations (GCK-MODY, n = 23), type 1 diabetes (n = 29), latent autoimmune diabetes in adults (LADA, n = 42), and type 2 diabetes (n = 206). Receiver operating characteristic curve analysis was performed to assess discriminative accuracy of 1,5AG for diabetes etiology.RESULTSMean (SD range) 1,5AG levels were: GCK-MODY 13.06 μg/ml (5.74–29.74), HNF1A-MODY 4.23 μg/ml (2.12–8.44), type 1 diabetes 3.09 μg/ml (1.45–6.57), LADA 3.46 μg/ml (1.42–8.45), and type 2 diabetes 5.43 (2.12–13.23). Levels in GCK-MODY were higher than in other groups (P < 10−4 vs. each group). HNF1A-MODY subjects showed no difference in unadjusted 1,5AG levels from type 2 diabetes, type 1 diabetes, and LADA. Adjusting for A1C revealed a difference between HNF1A-MODY and type 2 diabetes (P = 0.001). The discriminative accuracy of unadjusted 1,5AG levels was 0.79 for GCK-MODY versus type 2 diabetes and 0.86 for GCK-MODY versus HNF1A-MODY but was only 0.60 for HNF1A-MODY versus type 2 diabetes.CONCLUSIONSIn our dataset, serum 1,5AG performed well in discriminating GCK-MODY from other diabetes subtypes, particularly HNF1A-MODY. Measurement of 1,5AG levels could inform decisions regarding MODY diagnostic testing.

Polygenic Risk Variants for Type 2 Diabetes Susceptibility Modify Age at Diagnosis in Monogenic HNF1A Diabetes

OBJECTIVEMutations in the HNF1A gene are the most common cause of maturity-onset diabetes of the young (MODY). There is a substantial variation in the age at diabetes diagnosis, even within families where diabetes is caused by the same mutation. We investigated the hypothesis that common polygenic variants that predispose to type 2 diabetes might account for the difference in age at diagnosis.RESEARCH DESIGN AND METHODSFifteen robustly associated type 2 diabetes variants were successfully genotyped in 410 individuals from 203 HNF1A-MODY families, from two study centers in the U.K. and Norway. We assessed their effect on the age at diagnosis both individually and in a combined genetic score by summing the number of type 2 diabetes risk alleles carried by each patient.RESULTSWe confirmed the effects of environmental and genetic factors known to modify the age at HNF1A-MODY diagnosis, namely intrauterine hyperglycemia (−5.1 years if present, P = 1.6 × 10−10) and HNF1A mutation position (−5.2 years if at least two isoforms affected, P = 1.8 × 10−2). Additionally, our data showed strong effects of sex (females diagnosed 3.0 years earlier, P = 6.0 × 10−4) and age at study (0.3 years later diagnosis per year increase in age, P = 4.7 × 10−38). There were no strong individual single nucleotide polymorphism effects; however, in the combined genetic score model, each additional risk allele was associated with 0.35 years earlier diabetes diagnosis (P = 5.1 × 10−3).CONCLUSIONSWe show that type 2 diabetes risk variants of modest effect sizes reduce the age at diagnosis in HNF1A-MODY. This is one of the first studies to demonstrate that clinical characteristics of a monogenic disease can be modified by common polygenic variants.

Influence of Genetic Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Sulfonylurea Drugs

Sulfonylurea drugs including chlorpropamide, gliclazide, tolbutamide, glipizide, glibenclamide (glyburide) and glimepiride are the most widely used oral hypoglycaemic agents in people with type 2 diabetes. This review investigates the impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of sulfonylurea drugs. CYP2C9 is the major enzyme involved in sulfonylurea drug metabolism. CYP2C9 variant allele carriers have significant lower apparent clearance of these medicines. CYP2C19 genotype is more influential for gliclazide pharmacokinetics when compared to CYP2C9. Sulfonylurea pharmacodynamics is affected by several genes. Sulfonylurea receptor 1 (SUR1, ABCC8 gene) and K+ inward rectifier Kir6.2 (KCNJ11) have been correlated to significant variation in sulfonylurea response. Diabetics with the SUR1 exon 33 G allele are more sensitive to gliclazide and the rs5210 variant of the KCNJ11 gene was associated with improved clinical efficacy of gliclazide. Carriers of Transcription factor 7-like 2 (TCF7L2) variants are more likely to fail sulfonylurea therapy. On the other hand, patients with HNF-1alpha mutations had a significant greater response to gliclazide when compared to those with type 2 diabetes. The Arg972 polymorphism of insulin receptor substrate 1 (IRS1) may lead to secondary failure of sulfonylurea therapy. Calpain 10 gene (CAPN10) polymorphism has also been linked to sulfonylurea drug response. Despite the available evidence, larger population studies that investigate the pharmacokinetics and pharmacodynamics of sulfonylurea drugs are needed to investigate the influence of key SNPs amidst all potential contributing factors to variability in response to these which inturn will provide information to optimise sulfonylurea use in people with diabetes.

DNA hypomethylation, transient neonatal diabetes, and prune belly sequence in one of two identical twins

One known genetic mechanism for transient neonatal diabetes is loss of methylation at 6q24. The etiology of prune belly sequence is unknown but a genetic defect, affecting the mesoderm from which the triad abdominal muscle hypoplasia, urinary tract abnormalities, and cryptorchidism develop, has been suggested. We investigated a family, including one twin, with transient neonatal diabetes and prune belly sequence. Autoantibody tests excluded type 1 diabetes. Microsatellite marker analysis confirmed the twins being monozygotic. We identified no mutations in ZFP57, KCNJ11, ABCC8, GCK, HNF1A, HNF1B, HNF3B, IPF1, PAX4, or ZIC3. The proband had loss of methylation at the 6q24 locus TNDM and also at the loci IGF2R, DIRAS3, and PEG1, while the other family members, including the healthy monozygotic twin, had normal findings. The loss of methylation on chromosome 6q24 and elsewhere may indicate a generalized maternal hypomethylation syndrome, which accounts for both transient neonatal diabetes and prune belly sequence.

Maturity-Onset Diabetes of the Young in Children With Incidental Hyperglycemia:

OBJECTIVETo investigate the prevalence of maturity-onset diabetes of the young (MODY) in Italian children with incidental hyperglycemia.RESEARCH DESIGN AND METHODSAmong 748 subjects age 1–18 years with incidental hyperglycemia, minimal diagnostic criteria for MODY were met by 172 families. Mutational analyses of the glucokinase (GCK) and hepatocyte nuclear factor 1α (HNF1Α) genes were performed.RESULTSWe identified 85 GCK gene mutations in 109 probands and 10 HNF1Α mutations in 12 probands. In GCK patients, the median neonatal weight and age at the first evaluation were lower than those found in patients with HNF1A mutations. Median fasting plasma glucose and impaired fasting glucose/impaired glucose tolerance frequency after oral glucose tolerance testing were higher in GCK patients, who also showed a lower frequency of diabetes than HNF1A patients.CONCLUSIONSGCK mutations are the prevailing cause of MODY (63.4%) when the index case is recruited in Italian children with incidental hyperglycemia.

Hnf1alpha (MODY3) controls tissue-specific transcriptional programs and exerts opposed effects on cell growth in pancreatic islets and liver.

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. We demonstrate that Hnf1alpha can bind in a tissue-selective manner to genes that are expressed only in liver or islets. We also show that Hnf1alpha is essential only for the transcription of a minor fraction of its direct-target genes. Even among genes that were expressed in both liver and islets, the subset of targets showing functional dependence on Hnf1alpha was highly tissue specific. This was partly explained by the compensatory occupancy by the paralog Hnf1beta at selected genes in Hnf1a-deficient liver. In keeping with these findings, the biological consequences of Hnf1a deficiency were markedly different in islets and liver. Notably, Hnf1a deficiency led to impaired large-T-antigen-induced growth and oncogenesis in beta cells yet enhanced proliferation in hepatocytes. Collectively, these findings show that Hnf1alpha governs broad, highly tissue-specific genetic programs in pancreatic islets and liver and reveal key consequences of Hnf1a deficiency relevant to the pathophysiology of monogenic diabetes.

Mild fasting hyperglycemia in children: high rate of glucokinase mutations and some risk of developing type 1 diabetes mellitus

Incidental hyperglycemia in children generates concern about the presence of preclinical type 1 diabetes mellitus (T1DM). To genetically evaluate two common forms of maturity-onset diabetes of youth (MODY), the short-term prognosis in children with mild hyperglycemia, and a positive family history of diabetes mellitus. Asymptomatic children and adolescents (n = 14), younger than 15 yr, with fasting hyperglycemia, a positive family history of mild non-progressive hyperglycemia, and negative pancreatic autoantibodies were studied. Glucokinase gene (GCK) and hepatocyte nuclear factor 1 alpha gene (HNF1A) causing two common forms of MODY were sequenced. The clinical outcome was evaluated after a follow-up period of 2.8 +/- 1.3 yr. GCK mutations were present in seven children. The confirmation of this diagnosis allowed discontinuation of insulin in two families and oral medications in three families. Mutations of HNF1A were not detected in any of the families. During the follow-up period, all the GCK mutation carrier children remained asymptomatic without medication and the last hemoglobin A1c levels were 6.4 +/- 0.7%. In the GCK-negative children (n = 7), one developed T1DM, corresponding to 7.2% of the total group. Mild fasting hyperglycemia persisted during follow-up in four GCK-negative children and normalized in the remaining two. The presence of mild persistent hyperglycemia in any patient without autoantibodies should lead to genetic analysis of GCK, particularly if there is a positive family history. Furthermore, those without GCK mutations should be followed with repeat autoantibody testing, and other genetic types of diabetes should be considered if hyperglycemia worsens.

The genetic basis of congenital hyperinsulinism

Congenital hyperinsulinism (CHI) is biochemically characterised by the dysregulated secretion of insulin from pancreatic β-cells. It is a major cause of persistent hyperinsulinaemic hypoglycaemia (HH) in the newborn and infancy...

Advances in the diagnosis and management of hyperinsulinemic hypoglycemia

Hyperinsulinemic hypoglycemia (HH) is a consequence of unregulated insulin secretion by pancreatic beta-cells and is a major cause of hypoglycemic brain injury and mental retardation. Congenital HH is caused by mutations in genes involved in regulation of insulin secretion, seven of which have been identified (ABCC8, KCNJ11, GLUD1, CGK, HADH, SLC16A1 and HNF4A). Severe forms of congenital HH are caused by mutations in ABCC8 and KCNJ11, which encode the two components of the pancreatic beta-cell ATP-sensitive potassium channel. Mutations in HNF4A, GLUD1, CGK, and HADH lead to transient or persistent HH, whereas mutations in SLC16A1 cause exercise-induced HH. Rapid genetic analysis combined with an understanding of the histological features (focal or diffuse disease) of congenital HH and the introduction of (18)F-L-3,4-dihydroxyphenylalanine PET-CT to guide laparoscopic surgery have totally transformed the clinical approach to this complex disease. Adult-onset HH is mostly caused by an insulinoma; however, it has also been reported to present as postprandial HH in patients with noninsulinoma pancreatogenous hypoglycemia syndrome, in those who have undergone gastric-bypass surgery for morbid obesity, and in those with mutations in the insulin-receptor gene.

HNF1α mutations are present in half of clinically defined MODY patients in South-Brazilian individuals

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset, and pancreatic beta cell dysfunction. Heterozygous mutations in at least seven genes can cause MODY. In the present study we investigated the relative prevalence of GCK (glucokinase) and HNF1alpha (hepatocyte nuclear factor 1alpha) mutations, the more frequent causes of MODY, in 13 South-Brazilian families with multiple cases of diabetes consistent with MODY. Heterozygous variants in GCK and HNF1alpha genes were observed respectively in one (7.7%), and six (46.2%) families. The six HNF1alpha variants are likely to cause diabetes in the families where they were observed. However, we could not ascertain whether the GCK Gly117Ser variant found in one family is a causal mutation. In conclusion, we have confirmed in a South-Brazilian population that HNF1alpha mutations are a common cause of monogenic diabetes in adults selected with strict clinical diagnostic criteria.

Molecular background and clinical characteristics of HNF1A MODY in a Polish population

Purpose Knowing the molecular background of monogenic diabetes in affected individuals influences the clinical practice. Mutations in the HNF1A gene are the most frequent cause of MODY. The aim of the present study was to identify the genetic and clinical characteristics of HNF1A MODY in a Polish population, and the prevalence of diabetic complications and renal malformations. Methods We identified 47 families with the early-onset, autosomal-dominant form of diabetes that met the criteria of MODY. Mutation screening involved direct sequencing of the HNF1A gene. Patients’ characteristics included clinical data, anthropometric measurements and biochemical parameters. The search for renal malformations involved ultrasound examination of all HNF1A mutation carriers. Results We identified 13 HNF1A MODY families and examined 56 mutation carriers, including 46 diabetic patients. The average HbA 1c level among the diabetics was 7.5%. We identified diabetic retinopathy in 47.7% of the MODY patients, while diabetic nephropathy was present in 25%. In five HNF1A mutation carriers from three families, renal developmental malformations were identified, including one functioning kidney in two (3.6%) of them. Conclusion This first systematic search for HNF1A mutations in a Polish population revealed that they are a frequent cause of MODY. In this population, HNF1A mutation carriers were characterized by a high prevalence of diabetic complications. In addition, renal developmental abnormalities were found in some mutation carriers.

Role of HNF-1α and HNF-1β on insulin, IGF-1 and other potential target genes

Hepatocyte nuclear factor (HNF)-1α and HNF-1β are transcription factors that regulate many target genes in various tissues including liver, pancreas and kidney. Heterozygous mutations in the HNF-1α and HNF-1β genes result in maturity-onset diabetes of the young (MODY)3 and MODY5, respectively. The discovery of these ‘hepatocyte nuclear factors’ as MODY-responsible genes provided a breakthrough in the field of diabetes. Patients with HNF-1α and HNF-1β mutations, as well as their model mice, show impaired pancreatic β-cell function. The mechanism of impaired β-cell function and the target genes has been intensively investigated by considerable in vitro and in vivo studies. The insulin gene is one of the target genes of HNF-1α and HNF-1β in the β-cells, and may contribute to the diabetes. The IGF-1 gene is also regulated by HNF-1α and HNF-1β, and its decreased expression may contribute to growth failure and impaired β-cell proliferation. Mutations in HNF-1β result in symptoms in multiple organs, including kidney and liver, and several target genes have been reported to be involved in the pathogenesis. HNF-1α and HNF-1β may be one of the master regulators of hepatocyte and islet transcription, and further investigations by microarray and genome-scale analyses are providing information for the better understanding of the complex transcriptional network involving HNF-1α and -1β.

Reduced Pancreatic Volume in Hepatocyte Nuclear Factor 1A-Maturity-Onset Diabetes of the Young

There are interplays between the endocrine and exocrine pancreas. We recently reported an increased frequency of exocrine dysfunction in HNF1A-maturity-onset diabetes of the young (MODY3) patients, compared with controls. Reduced pancreatic volume is seen in HNF1B-MODY (MODY5) and diabetes types 1 and 2. The aim of this study was to investigate whether HNF1A mutation carriers have reduced pancreatic volume or abnormal pancreatic structure and whether any changes are associated with exocrine dysfunction. Fifteen HNF1A mutation carriers recruited from the Norwegian MODY Registry, 31 subjects with type 1 diabetes, 10 subjects with type 2 diabetes, and 11 controls underwent computed tomography of the pancreas. We measured pancreatic volume and X-ray attenuation. Pancreatic volume index was defined as pancreatic volume divided by body surface area. Pancreatic volume index was reduced in subjects with HNF1A-MODY (34.5 ml/m2; P < 0.02) and type 1 diabetes (21.4 ml/m2; P < 0.001) as compared with nondiabetic controls (45.7 ml/m2), and was reduced in subjects with diabetes in combination with fecal elastase deficiency (P = 0.03). Subjects with type 1 diabetes had smaller pancreatic volume index, compared with HNF1A mutation carriers (P < 0.001). Reduced pancreatic volume index was associated with increasing duration of diabetes. Pancreatic X-ray attenuation in HNF1A mutation carriers was not significantly different from that of nondiabetic controls. HNF1A mutation carriers have reduced pancreatic volume but less reduced than in patients with type 1 diabetes. Insulinopenia could explain both the pancreatic volume reduction and the associated pancreatic dysfunction.

Function of HNF1 in the pathogenesis of diabetes

The importance of hepatocyte nuclear factors (HNFs), as well as other transcription factors in β-cell development and function, was underlined by the characterization of human mutations causing maturity-onset diabetes of the young (MODY). HNF1A and HNF1B mutations lead to MODY forms 3 and 5, respectively. Thus, transcriptional control is an essential mechanism underlying the precise metabolic control exerted by β-cells in regulating insulin release. The diabetes phenotype of MODY3 (HNF1α) and the phenotypes of MODY5 (HNF1β), which can also include renal disease and genitourinary malformations, as well as neonatal diabetes and pancreatic agenesis, have now been described. However, detailed molecular pathology remains elusive. The large array of dominant-negative and deletion mutations, and the lack of structure–phenotype relationships for most mutations, have not helped us to formulate a mechanistic understanding. Further molecular studies of HNF1 actions and gene regulation are anticipated to provide useful insights into β-cell biology and potential therapeutic tools.

The Diabetic Phenotype in HNF4A Mutation Carriers Is Moderated By the Expression of HNF4A Isoforms From the P1 Promoter During Fetal Development

Mutations in the alternatively spliced HNF4A gene cause maturity-onset diabetes of the young (MODY). We characterized the spatial and developmental expression patterns of HNF4A transcripts in human tissues and investigated their role as potential moderators of the MODY phenotype. We measured the expression of HNF4A isoforms in human adult tissues and gestationally staged fetal pancreas by isoform-specific real-time PCR. The correlation between mutation position and age of diagnosis or age-related penetrance was assessed in a cohort of 190 patients with HNF4A mutations. HNF4A was expressed exclusively from the P2 promoter in adult pancreas, but from 9 weeks until at least 26 weeks after conception, up to 23% of expression in fetal pancreas was of P1 origin. HNF4A4-6 transcripts were not detected in any tissue. In whole pancreas, HNF4A9 expression was greater than in islets isolated from the endocrine pancreas (relative level 22 vs. 7%). Patients with mutations in exons 9 and 10 (absent from HNF4A3, HNF4A6, and HNF4A9 isoforms) developed diabetes later than those with mutations in exons 2-8, where all isoforms were affected (40 vs. 24 years; P = 0.029). Exon 9/10 mutations were also associated with a reduced age-related penetrance (53 vs. 10% without diabetes at age 55 years; P < 0.00001). We conclude that isoforms derived from the HNF4A P1 promoter are expressed in human fetal, but not adult, pancreas, and that their presence during pancreatic development may moderate the diabetic phenotype in individuals with mutations in the HNF4A gene.

Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young.

Aims/hypothesisMutations in the GCK and HNF1A genes are the most common cause of the monogenic forms of diabetes known as ‘maturity-onset diabetes of the young’. GCK encodes the glucokinase enzyme, which acts as the pancreatic glucose sensor, and mutations result in stable, mild fasting hyperglycaemia. A progressive insulin secretory defect is seen in patients with mutations in the HNF1A and HNF4A genes encoding the transcription factors hepatocyte nuclear factor-1 alpha and -4 alpha. A molecular genetic diagnosis often changes management, since patients with GCK mutations rarely require pharmacological treatment and HNF1A/4A mutation carriers are sensitive to sulfonylureas. These monogenic forms of diabetes are often misdiagnosed as type 1 or 2 diabetes. Best practice guidelines for genetic testing were developed to guide testing and reporting of results.MethodsA workshop was held to discuss clinical criteria for testing and the interpretation of molecular genetic test results. The participants included 22 clinicians and scientists from 13 countries. Draft best practice guidelines were formulated and edited using an online tool (http://www.coventi.com).ResultsAn agreed set of clinical criteria were defined for the testing of babies, children and adults for GCK, HNF1A and HNF4A mutations. Reporting scenarios were discussed and consensus statements produced.Conclusions/interpretationBest practice guidelines have been established for monogenic forms of diabetes caused by mutations in the GCK, HNF1A and HNF4A genes. The guidelines include both diagnostic and predictive genetic tests and interpretation of the results.For members of the EMQN MODY group see the Appendix. For details of their affiliations, see the Electronic supplementary material which is available to authorised users via the online version of this article (doi:10.1007/s00125-008-0942-y).

Persistent Hyperinsulinemic Hypoglycemia and Maturity-Onset Diabetes of the Young Due to Heterozygous HNF4A Mutations

Mutations in the human HNF4A gene encoding the hepatocyte nuclear factor (HNF)-4alpha are known to cause maturity-onset diabetes of the young (MODY), which is characterized by autosomal-dominant inheritance and impaired glucose-stimulated insulin secretion from pancreatic beta-cells. HNF-4alpha has a key role in regulating the multiple transcriptional factor networks in the islet. Recently, heterozygous mutations in the HNF4A gene were reported to cause transient hyperinsulinemic hypoglycemia associated with macrosomia. Three infants presented with macrosomia and severe hypoglycemia with a positive family history of MODY. The hypoglycemia was confirmed to be due to hyperinsulinism, and all three patients required diazoxide therapy to maintain normoglycemia. Two of the three infants are still requiring diazoxide therapy at 8 and 18 months, whereas one of them had resolution of hyperinsulinemic hypoglycemia at 32 months of age. Sequencing of the HNF4A gene identified heterozygous mutations in all three families. In family 1, a frameshift mutation L330fsdel17ins9 (c.987 1003del17ins9; p.Leu330fs) was present in the proband; a mutation affecting the conserved A nucleotide of the intron 2 branch site (c.264-21A>G) was identified in the proband of family 2; and finally a nonsense mutation, Y16X (c.48C>G, p.Tyr16X), was found in the proband of family 3. Heterozygous HNF4A mutations can therefore cause both transient and persistent hyperinsulinemic hypoglycemia associated with macrosomia. We recommend that macrosomic infants with transient or persistent hyperinsulinemic hypoglycemia should be screened for HNF4A mutations if there is a family history of youth-onset diabetes.