Dokument: Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants
| Titel: | Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=68375 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20250131-093520-6 | |||||||
| Kollektion: | Publikationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Texte » Artikel, Aufsatz | |||||||
| Medientyp: | Text | |||||||
| Autoren: | Welters, Alena [Autor] Nortmann, Oliver [Autor] Wörmeyer, Laura [Autor] Freiberg, Clemens [Autor] Eberhard, Daniel [Autor] Bachmann, Nadine [Autor] Bergmann, Carsten [Autor] Mayatepek, Ertan [Autor] | |||||||
| Dateien: |
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| Stichwörter: | hyperinsulinemic hypoglycemia, endoplasmic reticulum stress, intracellular calcium homeostasis, monogenic diabetes, BiP/GRP78 co-chaperone, calcium leak | |||||||
| Beschreibung: | 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. | |||||||
| Rechtliche Vermerke: | Originalveröffentlichung:
Welters, A., Nortmann, O., Wörmeyer, L., Freiberg, C., Eberhard, D., Bachmann, N., Bergmann, C., Mayatepek, E., Meißner, T., & Kummer, S. (2024). Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants. International Journal of Molecular Sciences, 25(2), Article 1270. https://doi.org/10.3390/ijms25021270 | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 31.01.2025 | |||||||
| Dateien geändert am: | 31.01.2025 |
