Sulfonylurea-Insensitive Permanent Neonatal Diabetes Caused by a Severe Gain-of-Function Tyr330His Substitution in Kir6.2

Conor McClenaghan, Novella Rapini, Domenico Umberto De Rose, Jian Gao, Jacob Roeglin, Carla Bizzarri, Riccardo Schiaffini, Eloisa Tiberi, Mafalda Mucciolo, Annalisa Deodati, Alessandro Perri, Giovanni Vento, Fabrizio Barbetti, Colin G. Nichols, Stefano Cianfarani

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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.

Original languageEnglish
Pages (from-to)215-223
Number of pages9
JournalHormone Research in Paediatrics
Issue number3
StatePublished - Aug 1 2022


  • Electrophysiology
  • Glibenclamide
  • Kchannel
  • Kir6.2
  • Permanent neonatal diabetes
  • SUR1
  • Sulfonylurea


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