Clinical and Molecular Characterization of a Dominant Form of Congenital Hyperinsulinism Caused by a Mutation in the High-Affinity Sulfonylurea Receptor

  1. Paul S. Thornton1,
  2. Courtney MacMullen1,
  3. Arupa Ganguly3,
  4. Eduardo Ruchelli2,
  5. Linda Steinkrauss,
  6. Ana Crane4,
  7. Lydia Aguilar-Bryan5 and
  8. Charles A. Stanley1
  1. 1Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  2. 2Division of Endocrinology and Department of Pathology, the Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  3. 3Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
  4. 4Department of Molecular and Cellular Biology, Division of Endocrinology, Baylor College of Medicine, Houston, Texas
  5. 5Department of Medicine, Division of Endocrinology, Baylor College of Medicine, Houston, Texas
  1. Address correspondencereprint requests to Charles A. Stanley, MD, Division of Endocrinology, Children’s Hospital of Philadelphia, 34th St. & Civic Center Boulevard, Philadelphia, PA 19104. E-mail stanleyc{at}


Recessive mutations of sulfonylurea receptor 1 (SUR1) and potassium inward rectifier 6.2 (Kir6.2), the two adjacent genes on chromosome 11p that comprise the β-cell plasma membrane ATP-sensitive K+ (KATP) channels, are responsible for the most common form of congenital hyperinsulinism in children. The present study was undertaken to identify the genetic defect in a family with dominantly inherited hyperinsulinism affecting five individuals in three generations. Clinical tests were carried out in three of the patients using acute insulin responses (AIRs) to intravenous stimuli to localize the site of defect in insulin regulation. The affected individuals showed abnormal positive calcium AIR, normal negative leucine AIR, subnormal positive glucose AIR, and impaired tolbutamide AIR. This AIR pattern suggested a KATP channel defect because it resembled that seen in children with recessive hyperinsulinism due to two common SUR1 mutations, g3992-9a and delPhe1388. Genetic linkage to the KATP locus was established using intragenic polymorphisms. Mutation analysis identified a novel trinucleotide deletion in SUR1 exon 34 that results in the loss of serine 1387. Studies of delSer1387 in COSm6 cells confirmed that the expressed mutant protein assembles with Kir6.2 and trafficks to the plasma membrane, but it had no 86Rb efflux ion transport activity. These results indicate that hyperinsulinism in this family is caused by a SUR1 mutation that is expressed dominantly rather than recessively.


    • Accepted May 22, 2003.
    • Received March 24, 2003.
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