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 journalArticle

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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.

Original languageEnglish
Pages (from-to)891-903
Number of pages13
JournalJournal of the American Society of Nephrology
Volume19
Issue number5
DOIs
Publication statusPublished - May 2008

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Kidney
Mutation
Zebrafish
Pronephros
Developmental Genes
Morpholinos
Organogenesis
Genes
Proteins

ASJC Scopus subject areas

  • Nephrology
  • Medicine(all)

Cite this

Weber, S., Taylor, J. C., Winyard, P., Baker, K. F., Sullivan-Brown, J., Schild, R., ... Burdine, R. D. (2008). SIX2 and BMP4 mutations associate with anomalous kidney development. Journal of the American Society of Nephrology, 19(5), 891-903. https://doi.org/10.1681/ASN.2006111282

SIX2 and BMP4 mutations associate with anomalous kidney development. / 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; Schaefer, Franz; Burdine, Rebecca D.

In: Journal of the American Society of Nephrology, Vol. 19, No. 5, 05.2008, p. 891-903.

Research output: Contribution to journalArticle

Weber, S, Taylor, JC, Winyard, P, Baker, KF, Sullivan-Brown, J, Schild, R, Knüppel, T, Zurowska, AM, Caldas-Alfonso, A, Litwin, M, Emre, S, Ghiggeri, GM, Bakkaloglu, A, Mehls, O, Antignac, C, Schaefer, F & Burdine, RD 2008, 'SIX2 and BMP4 mutations associate with anomalous kidney development', Journal of the American Society of Nephrology, vol. 19, no. 5, pp. 891-903. https://doi.org/10.1681/ASN.2006111282
Weber S, Taylor JC, Winyard P, Baker KF, Sullivan-Brown J, Schild R et al. SIX2 and BMP4 mutations associate with anomalous kidney development. Journal of the American Society of Nephrology. 2008 May;19(5):891-903. https://doi.org/10.1681/ASN.2006111282
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 ; Schaefer, Franz ; Burdine, Rebecca D. / SIX2 and BMP4 mutations associate with anomalous kidney development. In: Journal of the American Society of Nephrology. 2008 ; Vol. 19, No. 5. pp. 891-903.
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