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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^,||||, Escape Network^¶¶, Franz Schaefer^* and Rebecca D. Burdine

^* Pediatric Nephrology, University Children's Hospital Heidelberg, Germany; Department of Molecular Biology, Princeton University, New Jersey; Institute of Child Health, University College London, London, United Kingdom; Pediatric Nephrology Department, Medical University of Gdansk, Gdansk, Poland; ^|| Department of Pediatrics, Faculdade de Medicina do Porto, Porto, Portugal; ^¶ Nephrology and Kidney Transplantation Department, Children's Memorial Health Hospital, Warsaw, Poland; ^** Department of Pediatrics, Istanbul Medical Faculty, University of Istanbul, Istanbul, Turkey; Laboratory on Pathophysiology of Uremia, Istituto Giannina Gaslini, Genova, Italy; Hacettepe University Faculty of Medicine, Ankara, Turkey; Inserm U574, Hôpital Necker-Enfants Malades, Université René Descartes, Paris, France; and ^|||| Department of Genetics, Hôpital Necker-Enfants Malades, Université René Descartes, Paris, France

Correspondence: Dr. Franz Schaefer, Pediatric Nephrology Division, Hospital for Pediatric and Adolescent Medicine, University of Heidelberg, Im Neuenheimer Feld 150, 69120 Heidelberg, Germany. Phone: 49-6221-563-2396; Fax: 49-6221-56-4203; franz.schaefer{at}med.uni-heidelberg.de or Dr Rebecca D. Burdine, Department of Molecular Biology, Princeton University, Washington Road, Mof 433, Princeton, NJ 08544. Phone: 609-258-7515; Fax: 609-258-1343; rburdine{at}princeton.edu

Received for publication November 27, 2006. Accepted for publication October 3, 2007.

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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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673