Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4α mutations in a large European collection

Pearson, Ewan R.; Průhová, Štěpánka; Tack, Cees J.; Johansen, Anders; Castleden, H. A. J.; Lumb, P J; Wierzbicki, Anthony S.; Clark, P. M. S.; Lebl, Jan; Pedersen, Oluf; Ellard, Sian; Hansen, Torben; Hattersley, Andrew T.

doi:10.1007/s00125-005-1738-y

Cited by 214 publications

(188 citation statements)

References 49 publications

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“…However, there were no significant differences in triglyceride or lipoprotein(a) concentrations between carriers and controls in 42 subjects (mean BMI 25.3) from 11 families with a variety of HNF4A mutations in a large European collection [4], although six subjects (mean BMI 25.2) with the R154X mutations in another study had elevated lipoprotein(a) levels [5]. Various other apolipoprotein fractions (AI, AII, CIII, total HDL-cholesterol) have been reported to be significantly lower in subjects with various HNF4A mutations [2,4].Different mutations in the gene encoding glucokinase (GCK/MODY2) have also been associated with differences in apolipoprotein levels. In 15 German MODY2 carriers (A232D mutation, 12 subjects; V154fsdelTG mutation, three subjects) (mean BMI 24.4), the mean triglyceride concentration was 0.84 mmol/l [6].…”

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confidence: 84%

Phenotypic heterogeneity between different mutations of MODY subtypes and within MODY pedigrees

Fajans

Bell

2006

Diabetologia

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Contrary to currently held views [1], different mutations within the same MODY gene may be associated with differences in phenotype in diabetic as well as non-diabetic carrier subjects. This is illustrated by studies of apolipoproteins in different MODY1 pedigrees with various mutations of the gene encoding hepatocyte nuclear factor 4α (HNF4A). The mean plasma triglyceride concentration was significantly lower in 18 subjects (mean BMI 24.0) of the Michigan RW pedigree with the Q268X mutation (mean 0.80 mmol/l) [2] and in six subjects (mean BMI 24.0) from a Swedish family with the K99fsdelAA mutation (mean 0.64 mmol/l) [3] compared with 1.39 and 1.36 mmol/l, respectively, in control groups matched for BMI. The 18 RW subjects also had significantly lower lipoprotein(a) concentrations (mean 0.31 mmol/l) compared with the 24 control subjects (1.16 mmol/l). However, there were no significant differences in triglyceride or lipoprotein(a) concentrations between carriers and controls in 42 subjects (mean BMI 25.3) from 11 families with a variety of HNF4A mutations in a large European collection [4], although six subjects (mean BMI 25.2) with the R154X mutations in another study had elevated lipoprotein(a) levels [5]. Various other apolipoprotein fractions (AI, AII, CIII, total HDL-cholesterol) have been reported to be significantly lower in subjects with various HNF4A mutations [2,4].Different mutations in the gene encoding glucokinase (GCK/MODY2) have also been associated with differences in apolipoprotein levels. In 15 German MODY2 carriers (A232D mutation, 12 subjects; V154fsdelTG mutation, three subjects) (mean BMI 24.4), the mean triglyceride concentration was 0.84 mmol/l [6]. Two non-carrier subjects of the A232D pedigree had triglyceride levels of 1.17 and 1.25 mmol/l, suggesting that triglyceride levels may be lower in subjects with these two GCK mutations. The triglyceride level (mean 0.84 mmol/l) in the 15 MODY2 carriers is similar to that observed in 18 carriers of the RW/MODY1 pedigree (mean 0.80 mmol/l) [2]. In contrast, the triglyceride concentrations were normal in a very large series of primarily French MODY2 patients (mean BMI 22.0) [7]. We have recently studied a fourgeneration family (G pedigree) with a new GCK mutation, Leu 184 Pro (L184P). This pedigree includes affected individuals in three generations (ages 5-72 years). All are lean (mean BMI 21.3). In these six members, the mean triglyceride concentration was 0.68 mmol/l and the mean lipoprotein(a) concentration was 0.13 mmol/l, values that are lower than those in the RW/MODY1 pedigree. While the number of affected members in these various pedigrees is small, the results highlight the heterogeneity in apolipoprotein phenotypes seen in subjects with various HNF4A and GCK mutations. The variability could be due, at least in part, to different effects of the various mutations in each of these MODY genes on lipoprotein synthesis and metabolism but also to other genetic and environmental factors. Studies of larger numbers of pedigrees may determine if...

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confidence: 84%

Phenotypic heterogeneity between different mutations of MODY subtypes and within MODY pedigrees

Fajans

Bell

2006

Diabetologia

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“…The key difference in sulfonylurea treatment in neonatal diabetes is the high dose of glibenclamide required (0.45 mg/kg/day) 3 compared with the low doses in HNF1A/HNF4A MODY (<0.01 mg/kg/day) 1, 2 or typical doses in Type 2 diabetes (0.06–0.2 mg/kg/day) 32.…”

Section: Monogenic Diabetes Pregnancymentioning

confidence: 99%

Management of sulfonylurea‐treated monogenic diabetes in pregnancy: implications of placental glibenclamide transfer

et al. 2017

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The optimum treatment for HNF1A/HNF4A maturity‐onset diabetes of the young and ATP‐sensitive potassium (KATP) channel neonatal diabetes, outside pregnancy, is sulfonylureas, but there is little evidence regarding the most appropriate treatment during pregnancy. Glibenclamide has been widely used in the treatment of gestational diabetes, but recent data have established that glibenclamide crosses the placenta and increases risk of macrosomia and neonatal hypoglycaemia. This raises questions about its use in pregnancy. We review the available evidence and make recommendations for the management of monogenic diabetes in pregnancy. Due to the risk of stimulating increased insulin secretion in utero, we recommend that in women with HNF1A/ HNF4A maturity‐onset diabetes of the young, those with good glycaemic control who are on a sulfonylurea per conception either transfer to insulin before conception (at the risk of a short‐term deterioration of glycaemic control) or continue with sulfonylurea (glibenclamide) treatment in the first trimester and transfer to insulin in the second trimester. Early delivery is needed if the fetus inherits an HNF4A mutation from either parent because increased insulin secretion results in ~800‐g weight gain in utero, and prolonged severe neonatal hypoglycaemia can occur post‐delivery. If the fetus inherits a KATP neonatal diabetes mutation from their mother they have greatly reduced insulin secretion in utero that reduces fetal growth by ~900 g. Treating the mother with glibenclamide in the third trimester treats the affected fetus in utero, normalising fetal growth, but is not desirable, especially in the high doses used in this condition, if the fetus is unaffected. Prospective studies of pregnancy in monogenic diabetes are needed.

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“…The first group is subjects with other forms of MODY. Among those, the carriers of HNF-4␣ (MODY1) seem to be the most appropriate for the comparison because of its clinical similarity to HNF-1␣ MODY, relatively high frequency, and the lack of data on the altered glucose renal threshold (21,22). However, the families from The Polish Nationwide Registry of MODY have not been systematically tested for mutations in this gene, and we do not have a cohort of an appropriate size in this ethnic group.…”

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Clinical Application of 1,5-Anhydroglucitol Measurements in Patients with Hepatocyte Nuclear Factor-1α Maturity-Onset Diabetes of the Young

et al. 2008

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OBJECTIVE -1,5-anhydroglucitol (1,5-AG) is a short-term marker of metabolic control in diabetes. Its renal loss is stimulated in hyperglycemic conditions by glycosuria, which results in a lowered plasma concentration. As a low renal threshold for glucose has been described in hepatocyte nuclear factor-1␣ (HNF-1␣) maturity-onset diabetes of the young (MODY), the 1,5-AG level may be altered in these patients. The purpose of this study was to assess the 1,5-AG levels in patients with HNF-1␣ MODY and in type 2 diabetic subjects with a similar degree of metabolic control. In addition, we aimed to evaluate this particle as a biomarker for HNF-1␣ MODY.RESEARCH DESIGN AND METHODS -We included 33 diabetic patients from the Polish Nationwide Registry of MODY. In addition, we examined 43 type 2 diabetic patients and 47 nondiabetic control subjects. The 1,5-AG concentration was measured with an enzymatic assay (GlycoMark). Receiver operating characteristic (ROC) curve analysis was used to evaluate 1,5-AG as a screening marker for HNF-1␣ MODY.RESULTS -The mean 1,5-AG plasma concentration in diabetic HNF-1␣ mutation carriers was 5.9 g/ml, and it was lower than that in type 2 diabetic patients (11.0 g/ml, P ϭ 0.003) and in nondiabetic control subjects (23.9 g/ml, P Ͻ 0.00005). The ROC curve analysis revealed 85.7% sensitivity and 80.0% specificity of 1,5-AG in screening for HNF-1␣ MODY at the criterion of Ͻ6.5 g/ml in patients with an A1C level between 6.5 and 9.0%.CONCLUSIONS -1,5-AG may be a useful biomarker for differential diagnosis of patients with HNF-1␣ MODY with a specific range of A1C, although this requires further investigation. However, the clinical use of this particle in diabetic HNF-1␣ mutation carriers for metabolic control has substantial limitations.

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Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4α mutations in a large European collection

Cited by 214 publications

References 49 publications

Phenotypic heterogeneity between different mutations of MODY subtypes and within MODY pedigrees

Phenotypic heterogeneity between different mutations of MODY subtypes and within MODY pedigrees

Management of sulfonylurea‐treated monogenic diabetes in pregnancy: implications of placental glibenclamide transfer

Clinical Application of 1,5-Anhydroglucitol Measurements in Patients with Hepatocyte Nuclear Factor-1α Maturity-Onset Diabetes of the Young

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