Molecular Basis for Autosomal-Dominant Renal Fanconi Syndrome Caused by HNF4A
Valentina Marchesin,
Albert Pérez-Martí,
Gwenn Le Meur,
Roman Pichler,
Kelli Grand,
Enriko D. Klootwijk,
Anne Kesselheim,
Robert Kleta,
Soeren Lienkamp,
Matias Simons
Affiliations
Valentina Marchesin
INSERM UMR1163, Laboratory of Epithelial Biology and Disease, Imagine Institute, Paris Descartes University, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, 75015 Paris, France
Albert Pérez-Martí
INSERM UMR1163, Laboratory of Epithelial Biology and Disease, Imagine Institute, Paris Descartes University, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, 75015 Paris, France
Gwenn Le Meur
INSERM UMR1163, Laboratory of Epithelial Biology and Disease, Imagine Institute, Paris Descartes University, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, 75015 Paris, France
Roman Pichler
Renal Division, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79098 Freiburg, Germany
Kelli Grand
Institute of Anatomy, University of Zurich, 8057 Zurich, Switzerland
Enriko D. Klootwijk
Department of Renal Medicine, University College London, London NW3 2PF, UK
Anne Kesselheim
Department of Renal Medicine, University College London, London NW3 2PF, UK
Robert Kleta
Department of Renal Medicine, University College London, London NW3 2PF, UK
Soeren Lienkamp
Renal Division, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79098 Freiburg, Germany; Institute of Anatomy, University of Zurich, 8057 Zurich, Switzerland
Matias Simons
INSERM UMR1163, Laboratory of Epithelial Biology and Disease, Imagine Institute, Paris Descartes University, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, 75015 Paris, France; Corresponding author
Summary: 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. : 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.
