Sulfonylurea-Insensitive Permanent Neonatal Diabetes Caused by a Severe Gain-of-Function Tyr330His Substitution in Kir6.2.
Electrophysiology
Glibenclamide
KATP channel
Kir6.2
Permanent neonatal diabetes
SUR1
Sulfonylurea
Journal
Hormone research in paediatrics
ISSN: 1663-2826
Titre abrégé: Horm Res Paediatr
Pays: Switzerland
ID NLM: 101525157
Informations de publication
Date de publication:
2022
2022
Historique:
received:
27
08
2021
accepted:
02
12
2021
pubmed:
10
1
2022
medline:
9
8
2022
entrez:
9
1
2022
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND/AIMS
OBJECTIVE
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
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
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
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.
Identifiants
pubmed: 34999583
pii: 000521858
doi: 10.1159/000521858
pmc: PMC9259755
mid: NIHMS1779390
doi:
Substances chimiques
Blood Glucose
0
KATP Channels
0
Kir6.2 channel
0
Potassium Channels, Inwardly Rectifying
0
Sulfonylurea Compounds
0
Sulfonylurea Receptors
0
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
215-223Subventions
Organisme : NHLBI NIH HHS
ID : K99 HL150277
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL150277
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK109407
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL140024
Pays : United States
Informations de copyright
© 2022 S. Karger AG, Basel.
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