A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis

Yuting Guan; Xiujie Liang; Ziyuan Ma; Hailong Hu; Hongbo Liu; Zhen Miao; Andreas Linkermann; Jacklyn N Hellwege; Benjamin F Voight; Katalin Susztak

doi:10.1038/s41467-021-25377-x

A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis

Nat Commun. 2021 Aug 23;12(1):5078. doi: 10.1038/s41467-021-25377-x.

Authors

Yuting Guan^#^{1

2}, Xiujie Liang^#^{1

2}, Ziyuan Ma^{1

2}, Hailong Hu^{1

2}, Hongbo Liu^{1

2}, Zhen Miao^{1

2

3}, Andreas Linkermann^{4

5}, Jacklyn N Hellwege⁶, Benjamin F Voight^{2

7

8}, Katalin Susztak^{9

10}

Affiliations

¹ Department of Medicine, Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
² Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
³ Graduate group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁴ Division of Nephrology, Department of Internal Medicine, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
⁵ Biotechnology Center, Technische Universität Dresden, 01307, Dresden, Germany.
⁶ Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Nashville, TN, 37232, USA.
⁷ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁸ Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁹ Department of Medicine, Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. ksusztak@pennmedicine.upenn.edu.
¹⁰ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. ksusztak@pennmedicine.upenn.edu.

^# Contributed equally.

Abstract

Genome-wide association studies (GWAS) have identified loci for kidney disease, but the causal variants, genes, and pathways remain unknown. Here we identify two kidney disease genes Dipeptidase 1 (DPEP1) and Charged Multivesicular Body Protein 1 A (CHMP1A) via the triangulation of kidney function GWAS, human kidney expression, and methylation quantitative trait loci. Using single-cell chromatin accessibility and genome editing, we fine map the region that controls the expression of both genes. Mouse genetic models demonstrate the causal roles of both genes in kidney disease. Cellular studies indicate that both Dpep1 and Chmp1a are important regulators of a single pathway, ferroptosis and lead to kidney disease development via altering cellular iron trafficking.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood Urea Nitrogen
Chromatin / metabolism
Cisplatin
DNA Methylation / genetics
Dipeptidases / deficiency
Dipeptidases / genetics*
Dipeptidases / metabolism
Ferroptosis / genetics*
Folic Acid
Gene Editing
Gene Expression Regulation
Genetic Loci*
Genetic Predisposition to Disease*
Genome-Wide Association Study
Haploinsufficiency / genetics
Humans
Iron / metabolism
Kidney / pathology
Kidney Diseases / chemically induced
Kidney Diseases / genetics*
Mice
Necroptosis / genetics
Organ Specificity
Physical Chromosome Mapping
Pyroptosis / genetics
Quantitative Trait Loci
RNA, Messenger / genetics
RNA, Messenger / metabolism
Vesicular Transport Proteins / deficiency
Vesicular Transport Proteins / genetics*
Vesicular Transport Proteins / metabolism

Substances

CHMP1A protein, human
Chromatin
RNA, Messenger
Vesicular Transport Proteins
chmp1a protein, mouse
Folic Acid
Iron
Dipeptidases
dipeptidase
Cisplatin

Abstract

Publication types

MeSH terms

Substances

Grants and funding