The spectrum of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy.

Potassium channels in the plasma membrane of the pancreatic beta cells are critical in maintaining glucose homeostasis by responding to ATP and coupling metabolic changes to insulin secretion. These channels consist of subunits denoted the sulfonylurea receptor SUR1 and the inwardly rectifying ion channel KIR6.2, which are encoded by the genes ABCC8 and KCNJ11, respectively. Activating mutations in the subunit genes can result in monogenic diabetes, whereas inactivating mutations are the most common cause of congenital hyperinsulinism of infancy (CHI). Twenty-six Norwegian probands with CHI were analyzed for alterations in ABCC8 and KCNJ11. Fifteen probands (58%) had mutations in the ABCC8 gene. Nine patients were homozygous or compound heterozygous for the mutations, indicating diffuse pancreatic disease. In five patients, heterozygous and paternally inherited mutations were found, suggesting focal disease. One patient had a de novo mutation likely to cause a milder, dominant form of CHI. Altogether, 16 different ABCC8 mutations (including the novel alterations W231R, C267X, IVS6-3C>G, I462V, Q917X and T1531A) were identified. The mutations IVS10+1G>T, R1493W and V21D occurred in five, three and two families, respectively. KCNJ11 mutations were not found in any patients. Based on our mutation screening, we estimate the minimum birth prevalence of ABCC8-CHI in Norway to 1:70,000 during the past decade. Our results considerably extend the knowledge of the molecular genetics behind CHI in Scandinavia.

Prevalence of HNF1A (MODY3) mutations in a Norwegian population (the HUNT2 Study).

AIMS: Previous reports have indicated that maturity-onset diabetes of the young (MODY) caused by hepatocyte nuclear factor 1A (HNF1A) mutations (MODY3) is the most common MODY subtype in Northern Europe, but population-based prevalence estimates are lacking. We sought to determine the prevalence of HNF1A-MODY in diabetic subjects of a defined Norwegian population (the HUNT2 Study). METHODS: Of the 1972 diabetic HUNT2 subjects, we identified a subgroup of 43 suspected MODY cases based on information on family history, disease onset and anti-glutamic acid decarboxylase autoantibody status. These cases were considered a discovery group for HNF1A mutations and underwent full DNA sequencing. Subsequently, the entire cohort of diabetic HUNT2 subjects was screened for three selected HNF1A mutations. Possible founder effects were examined using the Norwegian MODY Registry. RESULTS: Three subjects from the discovery group harboured HNF1A mutations. Two subjects had the previously described R229Q mutation, one had a novel S6N alteration, whereas the HNF1A hot-spot mutation P291fsinsC was not identified. Genotyping the cohort of diabetic HUNT2 subjects identified five additional R229Q-positive subjects. Microsatellite analysis performed for all R229Q-positive probands of the Norwegian MODY Registry and those found in the HUNT2 population revealed that 17 of 18 (94%) had genotypes consistent with a common haplotype. CONCLUSIONS: Clinical MODY criteria were fulfilled in 2.2% of diabetic HUNT2 subjects. The minimum prevalence of HNF1A-MODY among diabetic HUNT2 subjects was 0.4%. Because of founder effects, registry-based prevalence studies probably need to be very large and they should also include prospectively collected phenotypes and extensive mutation screening to establish the true prevalence of MODY.