Author:
Riedhammer Korbinian M.,Nguyen Thanh-Minh T.,Koşukcu Can,Calzada-Wack Julia,Li Yong,Saygılı Seha,Wimmers Vera,Kim Gwang-Jin,Chrysanthou Marialena,Bakey Zeineb,Kraiger Markus,Sanz-Moreno Adrián,Amarie Oana V,Rathkolb Birgit,Klein-Rodewald Tanja,Garrett Lillian,Hölter Sabine M.,Seisenberger Claudia,Haug Stefan,Marschall Susan,Wurst Wolfgang,Fuchs Helmut,Gailus-Durner Valerie,Wuttke Matthias,Hrabe de Angelis Martin,Ćomić Jasmina,Akgün Doğan Özlem,Özlük Yasemin,Taşdemir Mehmet,Ağbaş Ayşe,Canpolat Nur,Çalışkan Salim,Weber Ruthild,Bergmann Carsten,Jeanpierre Cecile,Saunier Sophie,Lim Tze Y.,Hildebrandt Friedhelm,Alhaddad Bader,Wu Kaman,Antony Dinu,Matschkal Julia,Schaaf Christian,Renders Lutz,Schmaderer Christoph,Meitinger Thomas,Heemann Uwe,Köttgen Anna,Arnold Sebastian,Ozaltin Fatih,Schmidts Miriam,Hoefele Julia
Abstract
AbstractBackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below 30 years of age. Many monogenic forms have been discovered mainly due to comprehensive genetic testing like exome sequencing (ES). However, disease-causing variants in known disease-associated genes still only explain a proportion of cases. Aim of this study was to unravel the underlying molecular mechanism of syndromic CAKUT in two multiplex families with presumed autosomal recessive inheritance.Methods and ResultsES in the index individuals revealed two different rare homozygous variants inFOXD2,a transcription factor not previously implicated in CAKUT in humans: a frameshift in family 1 and a missense variant in family 2 with family segregation patterns consistent with autosomal-recessive inheritance. CRISPR/Cas9-derivedFoxd2knock-out (KO) mice presented with bilateral dilated renal pelvis accompanied by renal papilla atrophy while extrarenal features included mandibular, ophthalmologic, and behavioral anomalies, recapitulating the phenotype of humans withFOXD2dysfunction. To study the pathomechanism ofFOXD2-dysfunction-mediated developmental renal defects, in a complementary approach, we generated CRISPR/Cas9-mediated KO ofFoxd2in ureteric-bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important in renal/urogenital development, includingPax2andWnt4as well as gene expression changes indicating a cell identity shift towards a stromal cell identity. Histology ofFoxd2KO mouse kidneys confirmed increased fibrosis. Further, GWAS data (genome-wide association studies) suggests thatFOXD2could play a role for maintenance of podocyte integrity during adulthood.ConclusionsIn summary, our data implicate thatFOXD2dysfunction is a very rare cause of autosomal recessive syndromic CAKUT and suggest disturbances of the PAX2-WNT4 cell signaling axis contribute to this phenotype.
Publisher
Cold Spring Harbor Laboratory