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

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 Maturity-Onset Diabetes of the Young, type 1 (MODY1), one particular mutation (p.R85W) in the DNA binding domain (DBD) causes additional dysfunction of the renal proximal tubules or Fanconi renotubular syndrome (FRTS). Here, we find that the expression of the conserved fly ortholog dHNF4 harboring the FRTS mutation in Drosophila nephrocytes, a cell type with similarities to proximal tubular cells, 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. Both effects could be rescued by preventing nuclear export through interfering with serine phosphorylation in the DBD. Altogether, our data describe a genomic and 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.