Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants
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Le résumé fourni par la source
The BiP co-chaperone DNAJC3 protects cells during ER stress. In mice, the deficiency of DNAJC3 leads to beta-cell apoptosis and the gradual onset of hyperglycemia. In humans, biallelic DNAJC3 variants cause a multisystem disease, including early-onset diabetes mellitus. Recently, hyperinsulinemic hypoglycemia (HH) has been recognized as part of this syndrome. This report presents a case study of an individual with HH caused by DNAJC3 variants and provides an overview of the metabolic phenotype of individuals with HH and DNAJC3 variants. The study demonstrates that HH may be a primary symptom of DNAJC3 deficiency and can persist until adolescence. Additionally, glycemia and insulin release were analyzed in young DNACJ3 knockout (K.O.) mice, which are equivalent to human infants. In the youngest experimentally accessible age group of 4-week-old mice, the in vivo glycemic phenotype was already dominated by a reduced total insulin secretion capacity. However, on a cellular level, the degree of insulin release of DNAJC3 K.O. islets was higher during periods of increased synthetic activity (high-glucose stimulation). We propose that calcium leakage from the ER into the cytosol, due to disrupted DNAJC3-controlled gating of the Sec61 channel, is the most likely mechanism for HH. This is the first genetic mechanism explaining HH solely by the disruption of intracellular calcium homeostasis. Clinicians should screen for HH in DNAJC3 deficiency and consider DNAJC3 variants in the differential diagnosis of congenital hyperinsulinism.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants
- Date Crossref
- 20/01/2024
- Éditeur
- MDPI AG
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Düsseldorf University Hospital pays non établi dans la noticeÉtablissement de santé
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Heinrich Heine University Düsseldorf Institute of Metabolic Physiology pays non établi dans la noticeUniversité ou école supérieure
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Medical Faculty and University Hospital Düsseldorf Department of General Pediatrics pays non établi dans la noticeUniversité ou école supérieure
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University Medicine Göttingen Department of Pediatrics and Adolescent Medicine pays non établi dans la noticeUniversité ou école supérieure
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Medizinische Genetik Mainz pays non établi dans la noticeInstitution
Düsseldorf University Hospital, Institute of Metabolic Physiology — Heinrich Heine University Düsseldorf et Department of General Pediatrics — Medical Faculty and University Hospital Düsseldorf, avec 2 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.