Molecular Basis for Autosomal-Dominant Renal Fanconi Syndrome Caused by HNF4A

• Published in: Cell reports (Cambridge) 2019-12, Vol.29 (13), p.4407-4421.e5
• Main Authors: Marchesin, Valentina, Pérez-Martí, Albert, Le Meur, Gwenn, Pichler, Roman, Grand, Kelli, Klootwijk, Enriko D., Kesselheim, Anne, Kleta, Robert, Lienkamp, Soeren, Simons, Matias
• Format: Article
• Language: English
• Subjects: Animals; Cell Death; Cell Line; Cell Nucleus - metabolism; Cellular Reprogramming - genetics; Drosophila - genetics; Drosophila Proteins - genetics; Epithelial Cells - metabolism; Fanconi Syndrome - genetics; Fibroblasts - metabolism; Genes, Dominant; Hepatocyte Nuclear Factor 4 - genetics; Humans; Life Sciences; Lipid Droplets - metabolism; Lipid Droplets - ultrastructure; Mice; Mitochondria - metabolism; Mitochondria - ultrastructure; Mutation - genetics; Nephrons - metabolism; Nephrons - pathology; Phenotype; Proteolysis; Signal Transduction
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.11.066

HNF4A is a nuclear hormone receptor that binds DNA as an obligate homodimer. While all known human heterozygous mutations are associated with the autosomal-dominant diabetes form MODY1, one particular mutation (p.R85W) in the DNA-binding domain (DBD) causes additional renal Fanconi syndrome (FRTS). Here, we find that expression of the conserved fly ortholog dHNF4 harboring the FRTS mutation in Drosophila nephrocytes caused nuclear depletion and cytosolic aggregation of a wild-type dHNF4 reporter protein. While the nuclear depletion led to mitochondrial defects and lipid droplet accumulation, the cytosolic aggregates triggered the expansion of the endoplasmic reticulum (ER), autophagy, and eventually cell death. The latter effects could be fully rescued by preventing nuclear export through interfering with serine phosphorylation in the DBD. Our data describe a genomic and a non-genomic mechanism for FRTS in HNF4A-associated MODY1 with important implications for the renal proximal tubule and the regulation of other nuclear hormone receptors. [Display omitted] •HNF4 controls lipid metabolism in Drosophila nephrocytes•The kidney disease mutation R85W shows dominant-negative effects in nephrocytes•Dephosphorylation at S87 prevents the dominant-negative effects•R85W mutation causes mitochondrial dysfunction in reprogrammed renal epithelial cells Mutations in HNF4A cause the autosomal-dominant maturity-onset diabetes of the young type 1 (MODY1). One particular mutation in the DNA-binding domain, p.R85W, causes additional kidney defects. Using Drosophila nephrocytes as a model, Marchesin et al. show that this mutation causes lipid metabolism defects and mitochondrial dysfunction in a dominant-negative manner.