Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Institute of Clinical Pharmacology and Toxicology, Berlin Institute of Health, Berlin, Germany
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Institute of Clinical Pharmacology and Toxicology, Berlin Institute of Health, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Electrochemical Signaling in Development and Disease, Berlin, Germany
Nina Anne van de Lest
Department of Pathology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
Andreas Eisenreich
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Institute of Clinical Pharmacology and Toxicology, Berlin Institute of Health, Berlin, Germany
Martina Schmidbauer
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Institute of Clinical Pharmacology and Toxicology, Berlin Institute of Health, Berlin, Germany
Andrei Barysenka
Westfälische Wilhelms University, Genetic Epidemiology, Institute for Human Genetics, Münster, Germany
Bettina Purfürst
Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Core Facility Electron Microscopy, Berlin, Germany
Anje Sporbert
Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Advanced Light Microscopy, Berlin, Germany
Theodor Lorenzen
Institute of Clinical Pharmacology and Toxicology, Berlin Institute of Health, Berlin, Germany
Alexander M Meyer
Laura Herlan
Institute of Clinical Pharmacology and Toxicology, Berlin Institute of Health, Berlin, Germany
Anika Witten
Westfälische Wilhelms University, Genetic Epidemiology, Institute for Human Genetics, Münster, Germany
Frank Rühle
Westfälische Wilhelms University, Genetic Epidemiology, Institute for Human Genetics, Münster, Germany
Weibin Zhou
Division of Nephrology, Department of Medicine, Center for Human Disease Modeling, Duke University School of Medicine, Durham, United States
Emile de Heer
Department of Pathology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
Marion Scharpfenecker
Department of Pathology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
DZHK (German Centre for Cardiovascular Research), Partner site Berlin, Berlin, Germany
Monika Stoll
Westfälische Wilhelms University, Genetic Epidemiology, Institute for Human Genetics, Münster, Germany; Department of Biochemistry, Maastricht University, Genetic Epidemiology and Statistical Genetics, Maastricht, The Netherlands
Institute of Clinical Pharmacology and Toxicology, Berlin Institute of Health, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Berlin, Berlin, Germany
Unraveling the genetic susceptibility of complex diseases such as chronic kidney disease remains challenging. Here, we used inbred rat models of kidney damage associated with elevated blood pressure for the comprehensive analysis of a major albuminuria susceptibility locus detected in these models. We characterized its genomic architecture by congenic substitution mapping, targeted next-generation sequencing, and compartment-specific RNA sequencing analysis in isolated glomeruli. This led to prioritization of transmembrane protein Tmem63c as a novel potential target. Tmem63c is differentially expressed in glomeruli of allele-specific rat models during onset of albuminuria. Patients with focal segmental glomerulosclerosis exhibited specific TMEM63C loss in podocytes. Functional analysis in zebrafish revealed a role for tmem63c in mediating the glomerular filtration barrier function. Our data demonstrate that integrative analysis of the genomic architecture of a complex trait locus is a powerful tool for identification of new targets such as Tmem63c for further translational investigation.
