title: Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome.
abstract: Branchio-oto-renal syndrome (BOR) is an autosomal dominant developmental disorder characterized by the association of branchial arch defects, hearing loss, and renal anomalies. Mutations in EYA1 are known to cause BOR. More recently, mutations in SIX1, which interacts with EYA1, were identified as an additional cause of BOR. A second member of the SIX family of proteins, unc-39 (SIX5), has also been reported to directly interact with eya-1 in Caenorhabditis elegans. We hypothesized that this interaction would be conserved in humans and that interactors of EYA1 represent good candidate genes for BOR. We therefore screened a cohort of 95 patients with BOR for mutations in SIX5. Four different heterozygous missense mutations were identified in five individuals. Functional analyses of these mutations demonstrated that two mutations affect EYA1-SIX5 binding and the ability of SIX5 or the EYA1-SIX5 complex to activate gene transcription. We thereby identified heterozygous mutations in SIX5 as a novel cause of BOR.
authors.affiliation: Department of Pediatrics and of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Bethan E
authors.initials: BE
authors.lastname: Hoskins
authors.forename: Carl H
authors.initials: CH
authors.lastname: Cramer
authors.forename: Derek
authors.initials: D
authors.lastname: Silvius
authors.forename: Dan
authors.initials: D
authors.lastname: Zou
authors.forename: Richard M
authors.initials: RM
authors.lastname: Raymond
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Orten
authors.forename: William J
authors.initials: WJ
authors.lastname: Kimberling
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.forename: Dominique
authors.initials: D
authors.lastname: Weil
authors.forename: Christine
authors.initials: C
authors.lastname: Petit
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.forename: Pin-Xian
authors.initials: PX
authors.lastname: Xu
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D001483:Base Sequence; D019280:Branchio-Oto-Renal Syndrome / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008156:Luciferases; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C106687:SIX5 protein, human; D014157:Transcription Factors; D008156:Luciferases; C104381:EYA1 protein, human; D017027:Protein Tyrosine Phosphatases