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

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

Authors :
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
Source :
Horm Res Paediatr
Publication Year :
2022
Publisher :
S. Karger AG, 2022.

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.

Details

ISSN :
16632826 and 16632818
Volume :
95
Database :
OpenAIRE
Journal :
Hormone Research in Paediatrics
Accession number :
edsair.doi.dedup.....08f65aa623a6bf64bc1b279f3e9c2f0f
Full Text :
https://doi.org/10.1159/000521858