作者
Korbinian Riedhammer,Thanh-Minh T. Nguyen,Can Koşukçu,Julia Calzada‐Wack,Yong Li,Nurit Assia Batzir,Seha Saygılı,Vera Wimmers,Gwang-Jin Kim,Marialena Chrysanthou,Zeineb Bakey,Efrat Sofrin‐Drucker,Markus Kraiger,Adrián Sanz‐Moreno,Oana V. Amarie,Birgit Rathkolb,Tanja Klein-Rodewald,Lillian Garrett,Sabine M. Hölter,Claudia Seisenberger,Stefan Haug,Pascal Schlosser,Susan Marschall,Wolfgang Wurst,Helmut Fuchs,Valérie Gailus‐Durner,Matthias Wuttke,Martin Hrabé de Angelis,Jasmina Ćomić,Özlem Akgün Doğan,Yasemin Özlük,Mehmet Taşdemir,Ayşe Ağbaş,Nur Canpolat,Naama Orenstein,Salim Çalışkan,Ruthild G. Weber,Carsten Bergmann,C. Jeanpierre,Sophie Saunier,Tze Y. Lim,Friedhelm Hildebrandt,Bader Alhaddad,Lina Basel‐Salmon,Yael Borovitz,Kaman Wu,Dinu Antony,Julia Matschkal,Christian Schaaf,Lutz Renders,Christoph Schmaderer,Manuel Rogg,Christoph Schell,Thomas Meitinger,Uwe Heemann,Anna Köttgen,Sebastian J. Arnold,Fatih Özaltın,Miriam Schmidts,Julia Hoefele
摘要
Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below age 30 years. Many monogenic forms have been discovered due to comprehensive genetic testing like exome sequencing. However, disease-causing variants in known disease-associated genes only explain a proportion of cases. Here, we aim to unravel underlying molecular mechanisms of syndromic CAKUT in three unrelated multiplex families with presumed autosomal recessive inheritance. Exome sequencing in the index individuals revealed three different rare homozygous variants in FOXD2, encoding a transcription factor not previously implicated in CAKUT in humans: a frameshift in the Arabic and a missense variant each in the Turkish and the Israeli family with segregation patterns consistent with autosomal recessive inheritance. CRISPR/Cas9-derived Foxd2 knock-out mice presented with a bilateral dilated kidney pelvis accompanied by atrophy of the kidney papilla and mandibular, ophthalmologic, and behavioral anomalies, recapitulating the human phenotype. In a complementary approach to study pathomechanisms of FOXD2-dysfunction-mediated developmental kidney defects, we generated CRISPR/Cas9-mediated knock-out of Foxd2 in ureteric-bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important for kidney/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a shift towards a stromal cell identity. Histology of Foxd2 knock-out mouse kidneys confirmed increased fibrosis. Further, genome-wide association studies suggest that FOXD2 could play a role for maintenance of podocyte integrity during adulthood. Thus, our studies help in genetic diagnostics of monogenic CAKUT and in understanding of monogenic and multifactorial kidney diseases.