ArticleMolecular genetics & genomic medicine2019
HDAC4 mutations cause diabetes and induce β-cell FoxO1 nuclear exclusion.
Article in Molecular genetics & genomic medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 21 citations in OpenAlex.
- HDAC4: an emerging target in diabetes mellitus and diabetic complications.European journal of medical research · 2025Review
- Atypical KCNQ1/Kv7 channel function in a neonatal diabetes patient: Hypersecretion preceded the failure of pancreatic β-cells.iScience · 2024Article
- Exploring histone deacetylases in type 2 diabetes mellitus: pathophysiological insights and therapeutic avenues.Clinical epigenetics · 2024Review
- Roles of Histone Deacetylase 4 in the Inflammatory and Metabolic Processes.Diabetes & metabolism journal · 2024Review
- Heterozygous missense variant in GLI2 impairs human endocrine pancreas development.Nature communications · 2024Article
- Epigenetic Regulation of Pancreas Development and Function.Advances in anatomy, embryology, and cell biology · 2024Review
- Maternal obesity and gestational diabetes reprogram the methylome of offspring beyond birth by inducing epigenetic signatures in metabolic and developmental pathways.Cardiovascular diabetology · 2023Article
- Hyperglycemia Altered DNA Methylation Status and Impaired Pancreatic Differentiation from Embryonic Stem Cells.International journal of molecular sciences · 2021Article
- Review
- Inhibition of long non-coding RNA XIST upregulates microRNA-149-3p to repress ovarian cancer cell progression.Cell death & disease · 2021Article
- Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure.Molecular metabolism · 2020Article
- HDAC4 mutations cause diabetes and induce β-cell FoxO1 nuclear exclusion.Molecular genetics & genomic medicine · 2019Article
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Authors and funding
15 authors at 5 institutions in 3 countries.
Funding
Abstract
backgroundStudying patients with rare Mendelian diabetes has uncovered molecular mechanisms regulating β-cell pathophysiology. Previous studies have shown that Class IIa histone deacetylases (HDAC4, 5, 7, and 9) modulate mammalian pancreatic endocrine cell function and glucose homeostasis.
methodsWe performed exome sequencing in one adolescent nonautoimmune diabetic patient and detected one de novo predicted disease-causing HDAC4 variant (p.His227Arg). We screened our pediatric diabetes cohort with unknown etiology using Sanger sequencing. In mouse pancreatic β-cell lines (Min6 and SJ cells), we performed insulin secretion assay and quantitative RT-PCR to measure the β-cell function transfected with the detected HDAC4 variants and wild type. We carried out immunostaining and Western blot to investigate if the detected HDAC4 variants affect the cellular translocation and acetylation status of Forkhead box protein O1 (FoxO1) in the pancreatic β-cells.
resultsWe discovered three HDAC4 mutations (p.His227Arg, p.Asp234Asn, and p.Glu374Lys) in unrelated individuals who had nonautoimmune diabetes with various degrees of β-cell loss. In mouse pancreatic β-cell lines, we found that these three HDAC4 mutations decrease insulin secretion, down-regulate β-cell-specific transcriptional factors, and cause nuclear exclusion of acetylated FoxO1.
conclusionMutations in HDAC4 disrupt the deacetylation of FoxO1, subsequently decrease the β-cell function including insulin secretion, resulting in diabetes.
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