SIX2 and BMP4 mutations associate with anomalous kidney development

Stefanie Weber, Jaclyn C. Taylor, Paul Winyard, Kari F. Baker, Jessica Sullivan-Brown, Raphael Schild, Tanja Knüppel, Aleksandra M. Zurowska, Alberto Caldas-Alfonso, Mieczyslaw Litwin, Sevinc Emre, Gian Marco Ghiggeri, Aysin Bakkaloglu, Otto Mehls, Corinne Antignac, Franz Schaefer, Rebecca D. Burdine

Research output: Contribution to journalArticlepeer-review

167 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)891-903
Number of pages13
JournalJournal of the American Society of Nephrology
Issue number5
StatePublished - May 2008

All Science Journal Classification (ASJC) codes

  • General Medicine


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