title: Double homozygous missense mutations in DACH1 and BMP4 in a patient with bilateral cystic renal dysplasia.
abstract: Renal hypodysplasia (RHD) is characterized by small and/or disorganized kidneys following abnormal organogenesis. Mutations in several genes have been identified recently to be associated with RHD in humans, including BMP4, a member of the transforming growth factor (TGF)-β family of growth factors. DACH1 has been proposed as a candidate gene for RHD because of its involvement in the EYA-SIX-DACH network of renal developmental genes. Here, we present a patient with renal dysplasia carrying homozygous missense mutations in both BMP4 (p.N150K) and DACH1 (p.R684C). The genotype-phenotype correlation in the family hints at an oligogenic mode of inheritance of the disease in this kindred. Functional analyses of the identified DACH1 mutation in HEK293T cells demonstrated enhanced suppression of the TGF-β pathway suggesting that both mutations could act synergistically in the development of the phenotype in this patient. This finding provides a model for RHD as an oligo-/polygenic disorder and supports a role for DACH1 in the development of RHD in humans.
authors.affiliation: Department of Pediatric Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. rschild@uke.uni-hamburg.de
authors.forename: Raphael
authors.initials: R
authors.lastname: Schild
authors.forename: Tanja
authors.initials: T
authors.lastname: Knüppel
authors.forename: Martin
authors.initials: M
authors.lastname: Konrad
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.forename: Agnes
authors.initials: A
authors.lastname: Trautmann
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Kemper
authors.forename: Kongming
authors.initials: K
authors.lastname: Wu
authors.forename: Sergey
authors.initials: S
authors.lastname: Yaklichkin
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Richard
authors.initials: R
authors.lastname: Pestell
authors.forename: Dirk E
authors.initials: DE
authors.lastname: Müller-Wiefel
authors.forename: Franz
authors.initials: F
authors.lastname: Schaefer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weber
mesh_terms: D000328:Adult; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D056726:Genetic Association Studies; D006720:Homozygote; D006801:Humans; D007668:Kidney / Q000002:abnormalities*; D008297:Male; D020125:Mutation, Missense; D017044:Polycystic Kidney, Autosomal Recessive / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014564:Urogenital Abnormalities / Q000235:genetics*; D055815:Young Adult
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; C486747:DACH1 protein, human; D005136:Eye Proteins; D014157:Transcription Factors