Dataset Information

Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT).

ABSTRACT: 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 knockout 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 knockout 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 toward a stromal cell identity. Histology of Foxd2 knockout 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.

SUBMITTER: Riedhammer KM

PROVIDER: S-EPMC10957342 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT).

Riedhammer Korbinian M KM Nguyen Thanh-Minh T TT Koşukcu Can C Calzada-Wack Julia J Li Yong Y Assia Batzir Nurit N Saygılı Seha S Wimmers Vera V Kim Gwang-Jin GJ Chrysanthou Marialena M Bakey Zeineb Z Sofrin-Drucker Efrat E Kraiger Markus M Sanz-Moreno Adrián A Amarie Oana V OV Rathkolb Birgit B Klein-Rodewald Tanja T Garrett Lillian L Hölter Sabine M SM Seisenberger Claudia C Haug Stefan S Schlosser Pascal P Marschall Susan S Wurst Wolfgang W Fuchs Helmut H Gailus-Durner Valerie V Wuttke Matthias M Hrabe de Angelis Martin M Ćomić Jasmina J Akgün Doğan Özlem Ö Özlük Yasemin Y Taşdemir Mehmet M Ağbaş Ayşe A Canpolat Nur N Orenstein Naama N Çalışkan Salim S Weber Ruthild G RG Bergmann Carsten C Jeanpierre Cecile C Saunier Sophie S Lim Tze Y TY Hildebrandt Friedhelm F Alhaddad Bader B Basel-Salmon Lina L Borovitz Yael Y Wu Kaman K Antony Dinu D Matschkal Julia J Schaaf Christian W CW Renders Lutz L Schmaderer Christoph C Rogg Manuel M Schell Christoph C Meitinger Thomas T Heemann Uwe U Köttgen Anna A Arnold Sebastian J SJ Ozaltin Fatih F Schmidts Miriam M Hoefele Julia J

Kidney international 20231226 4

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. ...[more]

PMID: 38154558

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Project description:BackgroundCongenital 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 in FOXD2, 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-derived Foxd2 knock-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 with FOXD2 dysfunction. To study the pathomechanism of FOXD2-dysfunction-mediated developmental renal defects, in a complementary approach, we generated CRISPR/Cas9-mediated KO of Foxd2 in ureteric-bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important in renal/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a cell identity shift towards a stromal cell identity. Histology of Foxd2 KO mouse kidneys confirmed increased fibrosis. Further, GWAS data (genome-wide association studies) suggests that FOXD2 could play a role for maintenance of podocyte integrity during adulthood.ConclusionsIn summary, our data implicate that FOXD2 dysfunction is a very rare cause of autosomal recessive syndromic CAKUT and suggest disturbances of the PAX2-WNT4 cell signaling axis contribute to this phenotype.

Dataset Information

Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT).

Publications

Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT).

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