title: SIX2 and BMP4 mutations associate with anomalous kidney development.
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.
authors.affiliation: Pediatric Nephrology, University Children's Hospital Heidelberg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weber
authors.forename: Jaclyn C
authors.initials: JC
authors.lastname: Taylor
authors.forename: Paul
authors.initials: P
authors.lastname: Winyard
authors.forename: Kari F
authors.initials: KF
authors.lastname: Baker
authors.forename: Jessica
authors.initials: J
authors.lastname: Sullivan-Brown
authors.forename: Raphael
authors.initials: R
authors.lastname: Schild
authors.forename: Tanja
authors.initials: T
authors.lastname: Knüppel
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Zurowska
authors.forename: Alberto
authors.initials: A
authors.lastname: Caldas-Alfonso
authors.forename: Mieczyslaw
authors.initials: M
authors.lastname: Litwin
authors.forename: Sevinc
authors.initials: S
authors.lastname: Emre
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Ghiggeri
authors.forename: Aysin
authors.initials: A
authors.lastname: Bakkaloglu
authors.forename: Otto
authors.initials: O
authors.lastname: Mehls
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.forename: Escape
authors.initials: E
authors.lastname: Network
authors.forename: Franz
authors.initials: F
authors.lastname: Schaefer
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Burdine
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000002:abnormalities* / Q000502:physiology*; D008969:Molecular Sequence Data; D009399:Nephrons / Q000002:abnormalities / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051762:PAX2 Transcription Factor / Q000235:genetics; D010641:Phenotype; D051437:Renal Insufficiency / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D025721:WT1 Proteins / Q000235:genetics; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; C484762:SIX2 protein, human; D025721:WT1 Proteins; D029961:Zebrafish Proteins; C525813:bmp4 protein, zebrafish; C497320:pax2a protein, zebrafish; C484763:six2 protein, zebrafish