A novel mutation causing DEND syndrome

Objectives: Activating mutations in the human KCNJ11 gene, encoding the pore-forming subunit (Kir6.2) of the ATP-sensitive potassium (KATP) channel, are one cause of neonatal diabetes mellitus. In a few patients, KCNJ11 mutations cause a triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). The aim of this study was to determine the clinical effects, functional cause, and sensitivity to sulfonylurea treatment of a novel KCNJ11 mutation producing DEND syndrome. Methods: We screened the DNA of a 3-year-old patient with neonatal diabetes, severe developmental delay, and therapy-resistant epilepsy for mutations in KCNJ11. We carried out electrophysiologic analysis of wild-type and mutant KATP channels heterologously expressed in Xenopus oocytes. Results: We identified a novel Kir6.2 mutation (I167L) causing DEND syndrome. Functional analysis showed both homomeric and heterozygous mutant channels were less inhibited by MgATP leading to an increase in whole-cell KATP currents. This effect was due to an increase in the intrinsic open probability. Heterozygous channels were strongly inhibited by the sulfonylurea tolbutamide. Treatment of the patient with the sulfonylurea glibenclamide not only enabled insulin therapy to be stopped, but also resulted in improvement in epilepsy and psychomotor abilities. Conclusions: We report a case of developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome that shows neurologic improvement with sulfonylurea therapy. Early recognition of patients with DEND syndrome may have considerable therapeutic benefit for the patient.

[1]  F. Ashcroft,et al.  A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. , 2006, Human molecular genetics.

[2]  A. Hattersley,et al.  Kir6.2 mutations are a common cause of permanent neonatal diabetes in a large cohort of French patients. , 2004, Diabetes.

[3]  Robert Brenner,et al.  BK channel β4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures , 2005, Nature Neuroscience.

[4]  J. D. Baum,et al.  An imprinted gene(s) for diabetes? , 1995, Nature Genetics.

[5]  F. Ashcroft,et al.  Functional analysis of a structural model of the ATP‐binding site of the KATP channel Kir6.2 subunit , 2005, The EMBO journal.

[6]  F. Ashcroft,et al.  Crystal Structure of the Potassium Channel KirBac1.1 in the Closed State , 2003, Science.

[7]  I. Scheffer,et al.  Genetic dissection of the common epilepsies , 2006, Current opinion in neurology.

[8]  R. Scharfmann,et al.  Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. , 2006, The New England journal of medicine.

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

[10]  E. Perucca,et al.  An Introduction to Antiepileptic Drugs , 2005, Epilepsia.

[11]  A. Gloyn.  Glucokinase (GCK) mutations in hyper‐ and hypoglycemia: Maturity‐onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy , 2003, Human mutation.

[12]  A. Hattersley,et al.  Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene , 2006, Diabetologia.

[13]  F. Ashcroft,et al.  Functional effects of naturally occurring KCNJ11 mutations causing neonatal diabetes on cloned cardiac KATP channels , 2006, The Journal of physiology.

[14]  B. Neumcke,et al.  Cell-type specific depression of neuronal excitability in rat hippocampus by activation of ATP-sensitive potassium channels , 2002, European Biophysics Journal.

[15]  F. Ashcroft.  ATP-sensitive potassium channelopathies: focus on insulin secretion. , 2005, The Journal of clinical investigation.

[16]  F. Ashcroft,et al.  Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. , 2006, The New England journal of medicine.

[17]  Wolfgang Löscher,et al.  The neurobiology of antiepileptic drugs , 2004, Nature Reviews Neuroscience.

[18]  F. Ashcroft,et al.  Overlapping distribution of KATP channel‐forming Kir6.2 subunit and the sulfonylurea receptor SUR1 in rodent brain , 1997, FEBS letters.

[19]  C. Stafstrom.  Epilepsy: A Review of Selected Clinical Syndromes and Advances in Basic Science , 2006, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[20]  Jianmin Cui,et al.  Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder , 2005, Nature Genetics.

[21]  F. Ashcroft,et al.  Kir6.2 mutations causing neonatal diabetes provide new insights into Kir6.2–SUR1 interactions , 2005, The EMBO journal.

[22]  N. Rawson,et al.  Distribution and phenotype of neurons containing the ATP-sensitive K+ channel in rat brain , 1998, Brain Research.

[23]  F. Ashcroft,et al.  A gating mutation at the internal mouth of the Kir6.2 pore is associated with DEND syndrome , 2005, EMBO reports.

[24]  F. Ashcroft,et al.  A Kir6.2 Mutation Causing Neonatal Diabetes Impairs Electrical Activity and Insulin Secretion From INS-1 β-Cells , 2006, Diabetes.

[25]  D. McCormick,et al.  On the cellular and network bases of epileptic seizures. , 2001, Annual review of physiology.

[26]  F. Ashcroft,et al.  Perspectives in Diabetes Activating Mutations in Kir 6 . 2 and Neonatal Diabetes New Clinical Syndromes , New Scientific Insights , and New Therapy , 2005 .

[27]  R. D'Hooge,et al.  Pathophysiology of epilepsy. , 2000, Acta neurologica Belgica.

[28]  Y. Jan,et al.  A New ER Trafficking Signal Regulates the Subunit Stoichiometry of Plasma Membrane KATP Channels , 1999, Neuron.

[29]  A. Sólyom,et al.  Dose‐dependent Safety and Efficacy of Zonisamide: A Randomized, Double‐blind, Placebo‐controlled Study in Patients with Refractory Partial Seizures , 2005, Epilepsia.

[30]  B. Glaser,et al.  Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. , 2004, The Journal of clinical endocrinology and metabolism.

[31]  C. Nichols,et al.  An ATP-Binding Mutation (G334D) in KCNJ11 Is Associated With a Sulfonylurea-Insensitive Form of Developmental Delay, Epilepsy, and Neonatal Diabetes , 2007, Diabetes.

[32]  C. Nichols,et al.  The kinetic and physical basis of K(ATP) channel gating: toward a unified molecular understanding. , 2000, Biophysical journal.

[33]  F. Ashcroft,et al.  Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor , 1997, Nature.

[34]  F. Ashcroft,et al.  Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. , 2005, Diabetes.

[35]  F. Ashcroft,et al.  Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes , 2006, Pflügers Archiv.

[36]  A. Hattersley,et al.  KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features , 2006, European Journal of Human Genetics.

[37]  A. Konnerth,et al.  Cell-type specific expression of ATP-sensitive potassium channels in the rat hippocampus. , 1999, The Journal of physiology.

[38]  F. Ashcroft,et al.  Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. , 2004, The New England journal of medicine.

[39]  F. Ashcroft,et al.  Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[40]  T J Cole,et al.  British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. , 1998, Statistics in medicine.

[41]  A. Hattersley,et al.  Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. , 2004, Diabetes.

[42]  F. Ashcroft,et al.  Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP. , 2005, Human molecular genetics.