Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1.

ATP-sensitive potassium channels play a major role in linking metabolic signals to the exocytosis of insulin in the pancreatic beta 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 K(ATP) 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 and predisposes to later insulin deficiency.

[1]  Jaubert,et al.  Partial or near‐total pancreatectomy for persistent neonatal hyperinsulinaemic hypoglycaemia: the pathologist's role , 1998, Histopathology.

[2]  J. Ott,et al.  Strategies for multilocus linkage analysis in humans. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[3]  H. Aihara,et al.  Abnormalities of pancreatic islets by targeted expression of a dominant-negative KATP channel. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[4]  R. Reading,et al.  Cluster randomised trials in maternal and child health: implications for power and sample size , 2000, Archives of Disease in Childhood.

[5]  M. Permutt,et al.  Sequence Variants in the Pancreatic Islet β-Cell Inwardly Rectifying K+ Channel Kir6.2 (Bir) Gene: Identification and Lack of Role in Caucasian Patients with NIDDM , 1997, Diabetes.

[6]  M. Permutt,et al.  A Nonsense Mutation in the Inward Rectifier Potassium Channel Gene, Kir6.2, Is Associated With Familial Hyperinsulinism , 1997, Diabetes.

[7]  M. Permutt,et al.  Mutations in the sulonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. , 1996, Human molecular genetics.

[8]  C. Junien,et al.  Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy. , 1997, The Journal of clinical investigation.

[9]  F. Ashcroft,et al.  Tissue specificity of sulfonylureas: studies on cloned cardiac and beta-cell K(ATP) channels. , 1998, Diabetes.

[10]  F. Ashcroft,et al.  Properties and functions of ATP-sensitive K-channels. , 1990, Cellular signalling.

[11]  C. Stanley,et al.  Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. , 1998, The New England journal of medicine.

[12]  F M Matschinsky,et al.  Familial hyperinsulinism caused by an activating glucokinase mutation. , 1998, The New England journal of medicine.

[13]  A. Aynsley-Green.  NESIDIOBLASTOSIS OF THE PANCREAS IN INFANCY , 1981, Developmental medicine and child neurology.

[14]  C. Stanley,et al.  Hyperinsulinism caused by paternal-specific inheritance of a recessive mutation in the sulfonylurea-receptor gene. , 1999, Diabetes.

[15]  J. Bryan,et al.  Molecular biology of adenosine triphosphate-sensitive potassium channels. , 1999, Endocrine reviews.

[16]  R. DeFronzo,et al.  Glucose clamp technique: a method for quantifying insulin secretion and resistance. , 1979, The American journal of physiology.

[17]  J. Bryan,et al.  Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. , 1995, Science.

[18]  P. Smith,et al.  Cloning and functional expression of the cDNA encoding a novel ATP‐sensitive potassium channel subunit expressed in pancreatic β‐cells, brain, heart and skeletal muscle , 1995 .

[19]  C. Nichols,et al.  ATP inhibition of KATP channels: control of nucleotide sensitivity by the N‐terminal domain of the Kir6.2 subunit , 1999, The Journal of physiology.

[20]  E. Mayatepek,et al.  Persistent hyperinsulinaemic hypoglycaemia of infancy: therapy, clinical outcome and mutational analysis , 1997, European Journal of Pediatrics.

[21]  G. Edwards,et al.  The pharmacology of ATP-sensitive potassium channels. , 1993, Annual Review of Pharmacology and Toxicology.

[22]  F. Ashcroft,et al.  Electrophysiology of the pancreatic beta-cell. , 1989, Progress in biophysics and molecular biology.

[23]  C. Lindgren,et al.  High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes , 1999, Diabetologia.

[24]  M. Permutt,et al.  Adenosine Diphosphate as an Intracellular Regulator of Insulin Secretion , 1996, Science.

[25]  H. Huopio,et al.  A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland. , 1999, Diabetes.

[26]  C. Higgins,et al.  ABC transporters: from microorganisms to man. , 1992, Annual review of cell biology.

[27]  A. Whitelaw,et al.  Practical management of hyperinsulinism in infancy , 2001, Archives of disease in childhood. Fetal and neonatal edition.

[28]  C. Hales,et al.  Dual effects of diazoxide on ATP‐K+ currents recorded from an insulin‐secreting cell line , 1989, British journal of pharmacology.

[29]  C. Junien,et al.  Genetics of neonatal hyperinsulinism , 2000, Archives of disease in childhood. Fetal and neonatal edition.

[30]  T. Cole,et al.  A clinical comparison of SIDS and explained sudden infant deaths: how healthy and how normal? , 2000, Archives of disease in childhood.

[31]  C. Sempoux,et al.  Neonatal hyperinsulinemic hypoglycemia: heterogeneity of the syndrome and keys for differential diagnosis. , 1998, The Journal of clinical endocrinology and metabolism.

[32]  J. Ilonen,et al.  Impaired insulin secretion in non-diabetic offspring of probands with latent autoimmune diabetes mellitus in adults , 2000, Diabetologia.

[33]  E. Lightner,et al.  Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. , 1996, Human molecular genetics.

[34]  G. Bruining.  Recent advances in hyperinsulinism and the pathogenesis of diabetes mellitus , 1990 .

[35]  F. Ashcroft,et al.  The essential role of the Walker A motifs of SUR 1 in K-ATP channel activation by Mg-ADP and diazoxide result in the closure of K-ATP channels in the β-cell plasma , 1997 .

[36]  T. Fong,et al.  Nesidioblastosis of the pancreas. , 1990, American journal of clinical pathology.

[37]  T. Sekiya,et al.  Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Inazawa,et al.  Reconstitution of IKATP: An Inward Rectifier Subunit Plus the Sulfonylurea Receptor , 1995, Science.