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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
- 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.
- Subjects :
- Blood Glucose
endocrine system
Endocrinology, Diabetes and Metabolism
Infant, Newborn
nutritional and metabolic diseases
Sulfonylurea Receptors
Settore MED/38
Article
Infant, Newborn, Diseases
Settore MED/13
Sulfonylurea Compounds
Endocrinology
KATP Channels
Gain of Function Mutation
Pediatrics, Perinatology and Child Health
Diabetes Mellitus
Humans
Potassium Channels, Inwardly Rectifying
Child
hormones, hormone substitutes, and hormone antagonists
Subjects
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