Congenital anomalies of the kidney and the urinary tract (CAKUT) are the predominant cause for chronic kidney disease below age 30 years and the main cause of renal replacement therapy in children. The abnormalities are present from birth, and it is due to the abnormal development of the urinary system. In only ca 10% of the affected individuals, disease-causing variants in known disease associated genes can be identified.
In this international study led by clinicians and scientists from Germany, the Netherlands and Türkiye, the team was able to shed light on the impact of the transcription factor FOXD2 dysfunction on the CAKUT syndrome in humans. The results were published in Kidney International.
The starting point of the investigation was the discovery of rare homozygous variants in FOXD2 in individuals from three unrelated families with presumed autosomal recessive inheritance.
To investigate the consequences of Foxd2 dysfunction and to receive more evidence for FOXD2 as a potential player in CAKUT formation, Foxd2 knock-out mice were generated and comprehensively phenotyped. Microscopic analysis by standard hematoxylin and eosin staining revealed bilateral dilation of the renal pelvis accompanied by atrophy of the kidney papilla. Histology of kidneys confirmed increased fibrosis in Foxd2 KO animals. In addition, mandibular, ophthalmologic, and behavioral anomalies were observed, recapitulating the human phenotype of the syndrome.
To unravel the underlying patho-mechanisms of FOXD2- dysfunction–mediated developmental kidney defects, CRISPR/Cas9 knockout of Foxd2 in ureteric bud–induced mouse metanephric mesenchyme cells was induced. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important for kidney/urogenital development, including Pax2 and Wnt4. Pax2 protein levels in Foxd2-deficient cells were markedly reduced. Significantly lower rates of tubule formation were observed when using conditioned medium from Foxd2 mutant metanephric mesenchymal cells compared to conditioned medium from control cells, confirming the consequences of FOXD2 dysfunction. Further genome-wide association studies suggest that FOXD2 could play a role for maintenance of podocyte integrity during adulthood.
This multiple evidence points to the importance of transcription factor FOXD2 action for healthy kidney and urinary system development. The results of this study add knowledge to the understanding of the development of monogenetic and multifactorial kidney diseases and will help in genetic diagnostics of monogenetic CAKUT syndrome.
Riedhammer KM, Nguyen TT, Koşukcu C, Calzada-Wack J, Li Y, Assia Batzir N, Saygılı S, Wimmers V, Kim GJ, Chrysanthou M, Bakey Z, Sofrin-Drucker E, Kraiger M, Sanz-Moreno A, Amarie OV, Rathkolb B, Klein-Rodewald T, Garrett L, Hölter SM, Seisenberger C, Haug S, Schlosser P, Marschall S, Wurst W, Fuchs H, Gailus-Durner V, Wuttke M, Hrabe de Angelis M, Ćomić J, Akgün Doğan Ö, Özlük Y, Taşdemir M, Ağbaş A, Canpolat N, Orenstein N, Çalışkan S, Weber RG, Bergmann C, Jeanpierre C, Saunier S, Lim TY, Hildebrandt F, Alhaddad B, Basel-Salmon L, Borovitz Y, Wu K, Antony D, Matschkal J, Schaaf CW, Renders L, Schmaderer C, Rogg M, Schell C, Meitinger T, Heemann U, Köttgen A, Arnold SJ, Ozaltin F, Schmidts M, Hoefele J. Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT). Kidney Int. 2024 Apr;105(4):844-864. doi: 10.1016/j.kint.2023.11.032. Epub 2023 Dec 26.