Conor McClenaghan1,2, Novella Rapini3, Domenico Umberto De Rose4,5, Jian Gao1,2, Jacob Roeglin1,2, Carla Bizzarri3, Riccardo Schiaffini3, Eloisa Tiberi5, Mafalda Mucciolo6, Annalisa Deodati3, Alessandro Perri5, Giovanni Vento5,7, Fabrizio Barbetti3,8, Colin G Nichols1,2, Stefano Cianfarani3,9,10. 1. Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri, USA. 2. Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA. 3. Dipartimento Pediatrico Universitario Ospedaliero, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy. 4. Neonatal Intensive Care Unit, Medical and Surgical Department of Fetus - Newborn - Infant, "Bambino Gesù" Children's Hospital IRCCS, Rome, Italy. 5. Neonatal Intensive Care Unit, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Rome, Italy. 6. Genetics and Rare Disease Research Division, Bambino Gesù Pediatric Hospital, Rome, Italy. 7. Università Cattolica del Sacro Cuore, Rome, Italy. 8. Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy. 9. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. 10. Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm, Sweden.
Abstract
BACKGROUND/AIMS: Mutations in KCNJ11, the gene encoding the Kir6.2 subunit of pancreatic and neuronal KATP channels, are associated with a spectrum of neonatal diabetes diseases. METHODS: Variant screening was used to identify the cause of neonatal diabetes, and continuous glucose monitoring was used to assess effectiveness of sulfonylurea treatment. Electrophysiological analysis of variant KATP channel function was used to determine molecular basis. RESULTS: We identified a previously uncharacterized KCNJ11 mutation, c.988T>C [p.Tyr330His], in an Italian child diagnosed with sulfonylurea-resistant permanent neonatal diabetes and developmental delay (intermediate DEND). Functional analysis of recombinant KATP channels reveals that this mutation causes a drastic gain-of-function, due to a reduction in ATP inhibition. Further, we demonstrate that the Tyr330His substitution causes a significant decrease in sensitivity to the sulfonylurea, glibenclamide. CONCLUSIONS: In this subject, the KCNJ11 (c.988T>C) mutation provoked neonatal diabetes, with mild developmental delay, which was insensitive to correction by sulfonylurea therapy. This is explained by the molecular loss of sulfonylurea sensitivity conferred by the Tyr330His substitution and highlights the need for molecular analysis of such mutations.
BACKGROUND/AIMS: Mutations in KCNJ11, the gene encoding the Kir6.2 subunit of pancreatic and neuronal KATP channels, are associated with a spectrum of neonatal diabetes diseases. METHODS: Variant screening was used to identify the cause of neonatal diabetes, and continuous glucose monitoring was used to assess effectiveness of sulfonylurea treatment. Electrophysiological analysis of variant KATP channel function was used to determine molecular basis. RESULTS: We identified a previously uncharacterized KCNJ11 mutation, c.988T>C [p.Tyr330His], in an Italian child diagnosed with sulfonylurea-resistant permanent neonatal diabetes and developmental delay (intermediate DEND). Functional analysis of recombinant KATP channels reveals that this mutation causes a drastic gain-of-function, due to a reduction in ATP inhibition. Further, we demonstrate that the Tyr330His substitution causes a significant decrease in sensitivity to the sulfonylurea, glibenclamide. CONCLUSIONS: In this subject, the KCNJ11 (c.988T>C) mutation provoked neonatal diabetes, with mild developmental delay, which was insensitive to correction by sulfonylurea therapy. This is explained by the molecular loss of sulfonylurea sensitivity conferred by the Tyr330His substitution and highlights the need for molecular analysis of such mutations.
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