Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic <i>DNAJC3</i> Variants
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 <i>DNAJC3</i> variants cause a multisystem disease, including early-onset diabetes mellitus. Recently,...
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MDPI AG
2024-01-01
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| author | Alena Welters Oliver Nortmann Laura Wörmeyer Clemens Freiberg Daniel Eberhard Nadine Bachmann Carsten Bergmann Ertan Mayatepek Thomas Meissner Sebastian Kummer |
| author_facet | Alena Welters Oliver Nortmann Laura Wörmeyer Clemens Freiberg Daniel Eberhard Nadine Bachmann Carsten Bergmann Ertan Mayatepek Thomas Meissner Sebastian Kummer |
| author_sort | Alena Welters |
| collection | DOAJ |
| description | 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 <i>DNAJC3</i> 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 <i>DNAJC3</i> variants and provides an overview of the metabolic phenotype of individuals with HH and <i>DNAJC3</i> 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 <i>DNAJC3</i> variants in the differential diagnosis of congenital hyperinsulinism. |
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| language | English |
| last_indexed | 2024-03-08T09:52:27Z |
| publishDate | 2024-01-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-002ad8332aca42f882b49a9d746753ad2024-01-29T13:59:06ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-01-01252127010.3390/ijms25021270Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic <i>DNAJC3</i> VariantsAlena Welters0Oliver Nortmann1Laura Wörmeyer2Clemens Freiberg3Daniel Eberhard4Nadine Bachmann5Carsten Bergmann6Ertan Mayatepek7Thomas Meissner8Sebastian Kummer9Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, GermanyDepartment of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, GermanyDepartment of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, GermanyDepartment of Pediatrics and Adolescent Medicine, Pediatric Endocrinology, University Medicine Göttingen, D-37075 Göttingen, GermanyInstitute of Metabolic Physiology, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, GermanyMedizinische Genetik Mainz, Limbach Genetics, D-55128 Mainz, GermanyMedizinische Genetik Mainz, Limbach Genetics, D-55128 Mainz, GermanyDepartment of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, GermanyDepartment of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, GermanyDepartment of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, GermanyThe 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 <i>DNAJC3</i> 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 <i>DNAJC3</i> variants and provides an overview of the metabolic phenotype of individuals with HH and <i>DNAJC3</i> 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 <i>DNAJC3</i> variants in the differential diagnosis of congenital hyperinsulinism.https://www.mdpi.com/1422-0067/25/2/1270hyperinsulinemic hypoglycemiaendoplasmic reticulum stresscalcium leakintracellular calcium homeostasismonogenic diabetesBiP/GRP78 co-chaperone |
| spellingShingle | Alena Welters Oliver Nortmann Laura Wörmeyer Clemens Freiberg Daniel Eberhard Nadine Bachmann Carsten Bergmann Ertan Mayatepek Thomas Meissner Sebastian Kummer Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic <i>DNAJC3</i> Variants International Journal of Molecular Sciences hyperinsulinemic hypoglycemia endoplasmic reticulum stress calcium leak intracellular calcium homeostasis monogenic diabetes BiP/GRP78 co-chaperone |
| title | Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic <i>DNAJC3</i> Variants |
| title_full | Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic <i>DNAJC3</i> Variants |
| title_fullStr | Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic <i>DNAJC3</i> Variants |
| title_full_unstemmed | Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic <i>DNAJC3</i> Variants |
| title_short | Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic <i>DNAJC3</i> Variants |
| title_sort | congenital hyperinsulinism in humans and insulin secretory dysfunction in mice caused by biallelic i dnajc3 i variants |
| topic | hyperinsulinemic hypoglycemia endoplasmic reticulum stress calcium leak intracellular calcium homeostasis monogenic diabetes BiP/GRP78 co-chaperone |
| url | https://www.mdpi.com/1422-0067/25/2/1270 |
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