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Previous Volume 350:1838-1849 April 29, 2004 Number 18 Next

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ABSTRACT

Background Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K_ATP) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes.

Methods We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene.

Results Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K_ATP channels was greatly reduced.

Conclusions Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas.

Source Information

From the Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, United Kingdom (A.L.G., E.R.P., E.L.E., T.M.F., S.E., A.T.H.); the University Laboratory of Physiology, Oxford University, Oxford, United Kingdom (J.F.A., P.P., F.M.A.); Sophia Children's Hospital, Rotterdam, the Netherlands, (G.J.B., A.S.S.); the Institute of Endocrinology and Diabetes, Children's Hospital at Westmead, Westmead, Australia (N.H., S.S.); Piaui State University Medical School, Teresina, Piaui, Brazil (J.M.C.L.S.); the Institute for Clinical Medicine and Molecular Medicine, University of Bergen, Bergen, Norway (J.M., P.R.N.); Wessex Clinical Genetics Service and the Division of Human Genetics, Southampton University and Hospitals, National Health Service Trust, Southampton, United Kingdom (I.K.T.); Wessex Regional Genetics Laboratories, Salisbury District Hospital, Salisbury, United Kingdom (D.M.); Royal Hospital for Children, Bristol, United Kingdom (J.P.H.S.); Second Department of Pediatrics and Second Faculty of Medicine, Charles University, Prague, Czech Republic (Z.S.); Meander Medical Center, Amersfoort, the Netherlands (A.R.); Academic Unit of Child Health, Sheffield Children's Hospital, Sheffield, United Kingdom (J.K.H.W.); Regional Endocrine Laboratory, Birmingham, United Kingdom (P.C.); St. Luke's Hospital, Bradford, United Kingdom (S.G.); and the Division of Pediatric Endocrinology and Diabetes, Hackensack University Medical Center, Hackensack, N.J. (J.A.).

Address reprint requests to Dr. Hattersley at Diabetes and Vascular Medicine, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Rd., Exeter EX2 5AX, United Kingdom, or at a.t.hattersley{at}ex.ac.uk.

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