HDAC4 mutations cause diabetes and induce β-cell FoxO1 nuclear exclusion

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Rare Mendelian diabetes provides insights into beta-cell pathophysiology.
• Class IIa histone deacetylases (HDAC4, 5, 7, 9) influence pancreatic endocrine cell function and glucose homeostasis.

Purpose of the Study:

• To investigate the role of HDAC4 variants in nonautoimmune diabetes.
• To understand the molecular mechanisms by which HDAC4 mutations affect beta-cell function.

Main Methods:

• Exome and Sanger sequencing identified HDAC4 mutations in diabetic patients.
• In vitro studies using mouse pancreatic beta-cell lines assessed the impact of HDAC4 variants on insulin secretion and gene expression.
• Immunostaining and Western blot analyzed the effect of HDAC4 variants on FoxO1 acetylation and translocation.

Main Results:

• Three HDAC4 mutations (p.His227Arg, p.Asp234Asn, p.Glu374Lys) were found in unrelated individuals with nonautoimmune diabetes and beta-cell loss.
• HDAC4 mutations reduced insulin secretion, downregulated beta-cell-specific transcription factors, and caused nuclear exclusion of acetylated FoxO1 in mouse beta-cells.

Conclusions:

• HDAC4 mutations impair beta-cell function by disrupting FoxO1 deacetylation, leading to decreased insulin secretion and diabetes.
• This research highlights HDAC4 as a key regulator in pancreatic beta-cell function and identifies its mutations as a cause of nonautoimmune diabetes.