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Dominantly Inherited Hyperinsulinism Caused by a Mutation in the Sulfonylurea Receptor Type 1

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Dominantly Inherited Hyperinsulinism Caused by a Mutation in the Sulfonylurea Receptor Type 1 Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1 Hanna Huopio, … , Frances Ashcroft, Timo Otonkoski J Clin Invest. 2000;106(7):897-906. https://doi.org/10.1172/JCI9804. Article ATP-sensitive potassium channels play a major role in linking metabolic signals to the exocytosis of insulin in the pancreatic β cell. These channels consist of two types of protein subunit: the sulfonylurea receptor SUR1 and the inward rectifying potassium channel Kir6.2. Mutations in the genes encoding these proteins are the most common cause of congenital hyperinsulinism (CHI). Since 1973, we have followed up 38 pediatric CHI patients in Finland. We reported previously that a loss-of-function mutation in SUR1 (V187D) is responsible for CHI of the most severe cases. We have now identified a missense mutation, E1506K, within the second nucleotide binding fold of SUR1, found heterozygous in seven related patients with CHI and in their mothers. All patients have a mild form of CHI that usually can be managed by long-term diazoxide treatment. This clinical finding is in agreement with the results of heterologous coexpression studies of recombinant Kir6.2 and SUR1 carrying the E1506K mutation. Mutant KATP channels were insensitive to metabolic inhibition, but a partial response to diazoxide was retained. Five of the six mothers, two of whom suffered from hypoglycemia in infancy, have developed gestational or permanent diabetes. Linkage and haplotype analysis supported a dominant pattern of inheritance in a large pedigree. In conclusion, we describe the first dominantly inherited SUR1 mutation that causes CHI in early life […] Find the latest version: https://jci.me/9804/pdf Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1 Hanna Huopio,1 Frank Reimann,2 Rebecca Ashfield,2 Jorma Komulainen,1 Hanna-Liisa Lenko,3 Jaques Rahier,4 Ilkka Vauhkonen,5 Juha Kere,6 Markku Laakso,5 Frances Ashcroft,2 and Timo Otonkoski7 1Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland 2University Laboratory of Physiology, University of Oxford, Oxford, United Kingdom 3Department of Paediatrics, Tampere University Hospital, Tampere, Finland 4University Hospital St. Luc, Bruxelles, Belgium 5Department of Medicine, Kuopio University Hospital, Kuopio, Finland 6Finnish Genome Center, and 7Transplantation Laboratory, Haartman Institute, and the Hospital for Children and Adolescents, University of Helsinki, Finland Address correspondence to: Hanna Huopio, Department of Pediatrics , Kuopio University Hospital, PO Box 1777, 70211 Kuopio, Finland. Phone: 358-17-172380; Fax: 358-17-172410; E-mail: [email protected]. Received for publication March 7, 2000, and accepted in revised form August 28, 2000. ATP-sensitive potassium channels play a major role in linking metabolic signals to the exocytosis of insulin in the pancreatic β cell. These channels consist of two types of protein subunit: the sul- fonylurea receptor SUR1 and the inward rectifying potassium channel Kir6.2. Mutations in the genes encoding these proteins are the most common cause of congenital hyperinsulinism (CHI). Since 1973, we have followed up 38 pediatric CHI patients in Finland. We reported previously that a loss-of-function mutation in SUR1 (V187D) is responsible for CHI of the most severe cases. We have now identified a missense mutation, E1506K, within the second nucleotide binding fold of SUR1, found heterozygous in seven related patients with CHI and in their mothers. All patients have a mild form of CHI that usually can be managed by long-term diazoxide treatment. This clinical finding is in agreement with the results of heterologous coexpression studies of recombinant Kir6.2 and SUR1 carrying the E1506K mutation. Mutant KATP channels were insensitive to metabolic inhi- bition, but a partial response to diazoxide was retained. Five of the six mothers, two of whom suf- fered from hypoglycemia in infancy, have developed gestational or permanent diabetes. Linkage and haplotype analysis supported a dominant pattern of inheritance in a large pedigree. In conclusion, we describe the first dominantly inherited SUR1 mutation that causes CHI in early life and predis- poses to later insulin deficiency. J. Clin. Invest. 106:897–906 (2000). Introduction intracellular ATP concentration and a concomitant fall Congenital hyperinsulinism (CHI) is a rare genetic dis- in intracellular ADP. These nucleotide changes act syn- order characterized by a dysregulation of insulin secre- ergistically to close KATP channels, producing depolar- tion that leads to severe hypoglycemia. The severity of ization of the β-cell membrane, activation of voltage- the disease varies from a mild form, which responds to gated Ca2+ channels, and finally exocytosis of insulin. treatment with drugs (such as diazoxide) or hormones The KATP channel consists of two types of protein (like somatostatin), to a severe drug-resistant form, subunit: the sulfonylurea receptor SUR1 and the which may necessitate resection of the pancreas. Early inward rectifying potassium channel Kir6.2 (11). diagnosis is important to avoid irreversible brain dam- Mutations in the SUR1 gene are the major known age due to prolonged hypoglycemia (1–4). cause of CHI (5). However, a few mutations in Kir6.2 Mutations in four different genes have been associat- have also been found (6, 7). In most cases, the disease ed with CHI (5–10). Most mutations are associated appears to be diffuse, involving all β cells and occur- with the β-cell ATP-sensitive potassium (KATP) channel, ring throughout the pancreas. A focal form has also which plays a major role in the regulation of insulin been described, which is characterized by the somatic secretion. This channel is open in the unstimulated β loss of maternal alleles and is confined to focal ade- cell, and its activity keeps the resting membrane poten- nomatous lesions of the pancreas (12). All the SUR1 tial at a hyperpolarized (negative) level. An increase in and Kir6.2 mutations described so far have been the extracellular glucose concentration leads to inherited recessively. However, a gain-of-function increased β-cell metabolism and thus to a rise in the mutation in the glucokinase gene (GK) has been The Journal of Clinical Investigation | October 2000 | Volume 106 | Number 7 897 shown to cause a dominant form of CHI (8). Further- EDTA and were then diluted (1:1) with loading mix more, mutations in the glutamate dehydrogenase (95% formamide, 20 mM EDTA, 0.05% bromphenol gene cause CHI with hyperammonemia (9). blue, and 0.05% xylene cyanol). After denaturation at The overall incidence of CHI in Finland is 1:40,000, 98°C for 3 minutes, samples were immediately cooled which is about the same as that reported previously for on ice. A total of 3µl of each sample was loaded onto a Northern Europe (13, 14). The clinical phenotype of 5% (PCR products > 230 bp) or a 6% (PCR products < Finnish patients with CHI is variable. We have previous- 230 bp) nondenaturing polyacrylamide gel (acry- ly reported a founder mutation, V187D, in the SUR1 lamide/N,N-methylene-bis-acrylamide ratio 49:1) con- gene, which was detected in 15 Finnish patients with taining 10% of glycerol. The runs were performed at two CHI. This causes a severe form of CHI that results from different gel temperatures: 38°C for approximately 4 total inactivation of β-cell KATP channels (13). Efforts are hours and 29°C for 5 hours. Autoradiography was car- continuing to identify the genetic defects of the remain- ried out overnight at –70°C with intensifying screens. ing patients with CHI and to correlate the different Direct sequencing. Variant forms of DNA detected by genotypes and phenotypes. We report here a missense SSCP analysis were identified by direct sequencing SUR1 mutation that is associated with a mild, diazoxide- (Thermo Sequenase Radiolabeled Terminator Cycle responsive form of CHI and, for the first time to our Sequencing Kit; USB Corp., Cleveland, Ohio, USA) and knowledge, shows a dominant mode of inheritance. verified by restriction fragment length polymorphism analysis (RFLP) on a 3% agarose gel (NuSieve GTG; Methods FMC Bioproducts, Rockland, Maine, USA). Patients. All patients diagnosed with CHI at the Depart- Detection of mutation E1506K. To detect the mutation ments of Pediatrics of the five University Central Hos- E1506K, PCR amplification of genomic DNA was per- pitals of Finland since 1973 were included in this study. formed using the primers 5′-ATCCCATCTGCTCCACT- These patients are likely to represent all affected indi- CAC-3′ and 5′-ATCCCACTAAACCCTTTCCAG-3′. After viduals diagnosed during that time, but the possibility sequencing the SSCP variant, the mutant sequence was of single undiagnosed cases cannot be excluded. CHI confirmed by digestion of the 253-bp product with the was diagnosed using generally accepted criteria includ- restriction enzyme MnlI (New England Biolabs Inc., ing nonketotic hypoglycemia, inappropriately elevated Beverly, Massachusetts, USA). The PCR-product ampli- insulin levels, and an increased need for glucose admin- fied from 50 ng of genomic DNA was digested with 2 istration to prevent hypoglycemia (1, 4). U of the enzyme for 16 hours at 37°C and separated by Single-strand conformation polymorphism analysis. Periph- electrophoresis in 9% PAGE. The wild-type sequence eral blood samples were collected from all patients, and results in 105-bp, 61-bp, 33-bp, 29-bp, and 28-bp prod- DNA was prepared from blood leukocytes by pro- ucts. The mutation E1506K causes a disappearance of teinase K-phenol-chloroform extraction. The immedi- one of the restriction sites of MnlI and leads to the for- ate promoter region of SUR1 (220 bp upstream from mation of a new 89-bp product the transcriptional start site), all 39 SUR1 exons and Haplotype analysis. Three microsatellite markers flanking introns, the single exon of Kir6.2, the pro- D11S1890, D11S921, and D11S1888 were chosen for moter region (334 bp upstream from the transcrip- haplotype analysis.
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