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SIX2 and BMP4 mutations associate with anomalous kidney development
Authors:Weber Stefanie  Taylor Jaclyn C  Winyard Paul  Baker Kari F  Sullivan-Brown Jessica  Schild Raphael  Knüppel Tanja  Zurowska Aleksandra M  Caldas-Alfonso Alberto  Litwin Mieczyslaw  Emre Sevinc  Ghiggeri Gian Marco  Bakkaloglu Aysin  Mehls Otto  Antignac Corinne  Network Escape  Schaefer Franz  Burdine Rebecca D
Affiliation:Pediatric Nephrology, University Children's Hospital Heidelberg, Germany.
Abstract:
Renal hypodysplasia (RHD) is characterized by reduced kidney size and/or maldevelopment of the renal tissue following abnormal organogenesis. Mutations in renal developmental genes have been identified in a subset of affected individuals. Here, we report the first mutations in BMP4 and SIX2 identified in patients with RHD. We detected 3 BMP4 mutations in 5 RHD patients, and 3 SIX2 mutations in 5 different RHD patients. Overexpression assays in zebrafish demonstrated that these mutations affect the function of Bmp4 and Six2 in vivo. Overexpression of zebrafish six2.1 and bmp4 resulted in dorsalization and ventralization, respectively, suggesting opposing roles in mesendoderm formation. When mutant constructs containing the identified human mutations were overexpressed instead, these effects were attenuated. Morpholino knockdown of bmp4 and six2.1 affected glomerulogenesis, suggesting specific roles for these genes in the formation of the pronephros. In summary, these studies implicate conserved roles for Six2 and Bmp4 in the development of the renal system. Defects in these proteins could affect kidney development at multiple stages, leading to the congenital anomalies observed in patients with RHD.
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