PUBLICATION
SIX2 and BMP4 Mutations Associate With Anomalous Kidney Development
- Authors
- Weber, S., Taylor, J.C., Winyard, P., Baker, K.F., Sullivan-Brown, J., Schild, R., Knüppel, T., Zurowska, A.M., Caldas-Alfonso, A., Litwin, M., Emre, S., Ghiggeri, G.M., Bakkaloglu, A., Mehls, O., Antignac, C., Schaefer, F., and Burdine, R.D.
- ID
- ZDB-PUB-080306-31
- Date
- 2008
- Source
- Journal of the American Society of Nephrology : JASN 19(5): 891-903 (Journal)
- Registered Authors
- Baker, Kari, Burdine, Rebecca, Sullivan-Brown, Jessica
- Keywords
- none
- MeSH Terms
-
- Humans
- Zebrafish
- Kidney/abnormalities*
- Kidney/physiology*
- Genotype
- DNA Mutational Analysis
- Bone Morphogenetic Protein 4
- Nephrons/abnormalities
- Nephrons/physiology
- Animals
- Gene Expression Regulation, Developmental
- Amino Acid Sequence
- Phenotype
- Molecular Sequence Data
- PAX2 Transcription Factor/genetics
- Bone Morphogenetic Proteins/genetics*
- Zebrafish Proteins/genetics
- Nerve Tissue Proteins/genetics*
- Renal Insufficiency/genetics*
- Renal Insufficiency/pathology*
- Renal Insufficiency/physiopathology
- Disease Models, Animal
- WT1 Proteins/genetics
- Homeodomain Proteins/genetics*
- PubMed
- 18305125 Full text @ J. Am. Soc. Nephrol.
Citation
Weber, S., Taylor, J.C., Winyard, P., Baker, K.F., Sullivan-Brown, J., Schild, R., Knüppel, T., Zurowska, A.M., Caldas-Alfonso, A., Litwin, M., Emre, S., Ghiggeri, G.M., Bakkaloglu, A., Mehls, O., Antignac, C., Schaefer, F., and Burdine, R.D. (2008) SIX2 and BMP4 Mutations Associate With Anomalous Kidney Development. Journal of the American Society of Nephrology : JASN. 19(5):891-903.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping