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


Marchesin, Valentina; Pérez-Martí, Albert; Le Meur, Gwenn; Pichler, Roman; Grand, Kelli; Klootwijk, Enriko D; Kesselheim, Anne; Kleta, Robert; Lienkamp, Soeren; Simons, Matias (2019). Molecular Basis for Autosomal-Dominant Renal Fanconi Syndrome Caused by HNF4A. Cell Reports, 29(13):4407-4421.e5.

Abstract

HNF4A is a nuclear hormone receptor that bindsDNA as an obligate homodimer. While all known hu-man heterozygous mutations are associated with theautosomal-dominant diabetes form MODY1, oneparticular mutation (p.R85W) in the DNA-bindingdomain (DBD) causes additional renal Fanconi syn-drome (FRTS). Here, we find that expression of theconserved fly ortholog dHNF4 harboring the FRTSmutation inDrosophilanephrocytes caused nucleardepletion and cytosolic aggregation of a wild-typedHNF4 reporter protein. While the nuclear depletionled to mitochondrial defects and lipid droplet accu-mulation, the cytosolic aggregates triggered theexpansion of the endoplasmic reticulum (ER), auto-phagy, and eventually cell death. The latter effectscould be fully rescued by preventing nuclear exportthrough interfering with serine phosphorylation inthe DBD. Our data describe a genomic and a non-genomic mechanism for FRTS in HNF4A-associatedMODY1 with important implications for the renalproximal tubule and the regulation of other nuclearhormone receptors.

Abstract

HNF4A is a nuclear hormone receptor that bindsDNA as an obligate homodimer. While all known hu-man heterozygous mutations are associated with theautosomal-dominant diabetes form MODY1, oneparticular mutation (p.R85W) in the DNA-bindingdomain (DBD) causes additional renal Fanconi syn-drome (FRTS). Here, we find that expression of theconserved fly ortholog dHNF4 harboring the FRTSmutation inDrosophilanephrocytes caused nucleardepletion and cytosolic aggregation of a wild-typedHNF4 reporter protein. While the nuclear depletionled to mitochondrial defects and lipid droplet accu-mulation, the cytosolic aggregates triggered theexpansion of the endoplasmic reticulum (ER), auto-phagy, and eventually cell death. The latter effectscould be fully rescued by preventing nuclear exportthrough interfering with serine phosphorylation inthe DBD. Our data describe a genomic and a non-genomic mechanism for FRTS in HNF4A-associatedMODY1 with important implications for the renalproximal tubule and the regulation of other nuclearhormone receptors.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Anatomy
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > General Biochemistry, Genetics and Molecular Biology
Uncontrolled Keywords:General Biochemistry, Genetics and Molecular Biology
Language:English
Date:24 December 2019
Deposited On:16 Jan 2020 10:03
Last Modified:22 Apr 2020 21:57
Publisher:Cell Press (Elsevier)
ISSN:2211-1247
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.celrep.2019.11.066
PubMed ID:31875549
Project Information:
  • : FunderH2020
  • : Grant ID804474
  • : Project TitleDiRECT - Directly reprogrammed renal cells for targeted medicine

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