Sulfonylurea-Insensitive Permanent Neonatal Diabetes Caused by a Severe Gain-of-Function Tyr330His Substitution in Kir6.2.
Horm Res Paediatr
; 95(3): 215-223, 2022.
Article
em En
| MEDLINE
| ID: mdl-34999583
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Canais de Potássio Corretores do Fluxo de Internalização
/
Diabetes Mellitus
/
Doenças do Recém-Nascido
Tipo de estudo:
Prognostic_studies
Limite:
Child
/
Humans
/
Newborn
Idioma:
En
Revista:
Horm Res Paediatr
Assunto da revista:
ENDOCRINOLOGIA
/
PEDIATRIA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos