Congenital Hyperinsulinism and Glucose Hypersensitivity in Homozygous and Heterozygous Carriers of Kir6.2 (KCNJ11) Mutation V290M Mutation

KATP Channel Inactivation Mechanism and Clinical Management

  1. Colin G. Nichols2
  1. 1Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina;
  2. 2Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri;
  3. 3Unit of Metabolic Diseases, Department of Pediatrics, Bambino Gesù Children's Hospital, Rome, Italy;
  4. 4Unit of Nuclear Medicine, Department of Radiology, Bambino Gesù Children's Hospital, Rome, Italy;
  5. 5Department of Nuclear Medicine, Catholic University of the Sacred Heart, Rome, Italy;
  6. 6Department of Surgery, Bambino Gesù Children's Hospital, Rome, Italy;
  7. 7Laboratory of Monogenic Diabetes, Bambino Gesù Children's Hospital Istituto Di Ricovero e Cura a Carattere Scientifico, Rome, Italy;
  8. 8Department of Internal Medicine, University of Tor Vergata, and Laboratory of Monogenic Diabetes, Bambino Gesù Children's Hospital Istituto Di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
  1. Corresponding authors: Colin G. Nichols, cnichols{at}, and Fabrizio Barbetti, mody.2{at}
  • †Deceased.

  1. K.J.L. and A.A. contributed equally to this study.


OBJECTIVE The ATP-sensitive K+ channel (KATP) controls insulin secretion from the islet. Gain- or loss-of-function mutations in channel subunits underlie human neonatal diabetes and congenital hyperinsulinism (HI), respectively. In this study, we sought to identify the mechanistic basis of KATP-induced HI in two probands and to characterize the clinical course.

RESEARCH DESIGN AND METHODS We analyzed HI in two probands and characterized the course of clinical treatment in each, as well as properties of mutant KATP channels expressed in COSm6 cells using Rb efflux and patch-clamp methods.

RESULTS We identified mutation V290M in the pore-forming Kir6.2 subunit in each proband. In vitro expression in COSm6 cells supports the mutation resulting in an inactivating phenotype, which leads to significantly reduced activity in intact cells when expressed homomerically, and to a lesser extent when expressed heteromerically with wild-type subunits. In one heterozygous proband, a fluoro-DOPA scan revealed a causal focal lesion, indicating uniparental disomy with loss of heterozygosity. In a second family, the proband, homozygous for the mutation, was diagnosed with severe diazoxide–unresponsive hypersinsulinism at 2 weeks of age. The patient continues to be treated successfully with octreotide and amlodipine. The parents and a male sibling are heterozygous carriers without overt clinical HI. Interestingly, both the mother and the sibling exhibit evidence of abnormally enhanced glucose tolerance.

CONCLUSIONS V290M results in inactivating KATP channels that underlie HI. Homozygous individuals may be managed medically, without pancreatectomy. Heterozygous carriers also show evidence of enhanced glucose sensitivity, consistent with incomplete loss of KATP channel activity.


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  • Received May 22, 2010.
  • Accepted October 15, 2010.

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