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Genotype-Phenotype Correlations in Children with Congenital Hyperinsulinism Due to Recessive Mutations of the Adenosine Triphosphate-Sensitive Potassium Channel Genes

Division of Endocrinology/Diabetes (M.J.H., A.K., C.M., C.A.S.) and General Clinical Research Center (P.B.), The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104; Department of Genetics (A.G.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; and Division of Endocrinology (P.S.T.), Cook Children’s Medical Center, Fort Worth, Texas 76104

Address all correspondence and requests for reprints to: Charles A. Stanley, M.D., Division of Endocrinology/Diabetes, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, Pennsylvania 19104. E-mail: stanleyc{at}email.chop.edu.

Congenital hyperinsulinism (HI) is most commonly caused by recessive mutations of the pancreatic ß-cell ATP-sensitive potassium channel (K_ATP), encoded by two genes on chromosome 11p, SUR1 and Kir6.2. The two mutations that have been best studied, SUR1 g3992-9a and SUR1 delF1388, are null mutations yielding nonfunctional channels and are characterized by nonresponsiveness to diazoxide, a channel agonist, and absence of acute insulin responses (AIRs) to tolbutamide, a channel antagonist, or leucine. To examine phenotypes of other K_ATP mutations, we measured AIRs to calcium, leucine, glucose, and tolbutamide in infants with recessive SUR1 or Kir6.2 mutations expressed as diffuse HI (n = 8) or focal HI (n = 14). Of the 24 total mutations, at least seven showed evidence of residual K_ATP channel function. This included positive AIR to both tolbutamide and leucine in diffuse HI cases or positive AIR to leucine in focal HI cases. One patient with partial K_ATP function also responded to treatment with the channel agonist, diazoxide. Six of the seven patients with partial defects had amino acid substitutions or insertions; whereas, the other patient was compound heterozygous for two premature stop codons. These results indicate that some K_ATP mutations can yield partially functioning channels, including cases of hyperinsulinism that are fully responsive to diazoxide therapy.

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