title: SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.
abstract: Urinary tract malformations constitute the most frequent cause of chronic renal failure in the first two decades of life. Branchio-otic (BO) syndrome is an autosomal dominant developmental disorder characterized by hearing loss. In branchio-oto-renal (BOR) syndrome, malformations of the kidney or urinary tract are associated. Haploinsufficiency for the human gene EYA1, a homologue of the Drosophila gene eyes absent (eya), causes BOR and BO syndromes. We recently mapped a locus for BOR/BO syndrome (BOS3) to human chromosome 14q23.1. Within the 33-megabase critical genetic interval, we located the SIX1, SIX4, and SIX6 genes, which act within a genetic network of EYA and PAX genes to regulate organogenesis. These genes, therefore, represented excellent candidate genes for BOS3. By direct sequencing of exons, we identified three different SIX1 mutations in four BOR/BO kindreds, thus identifying SIX1 as a gene causing BOR and BO syndromes. To elucidate how these mutations cause disease, we analyzed the functional role of these SIX1 mutations with respect to protein-protein and protein-DNA interactions. We demonstrate that all three mutations are crucial for Eya1-Six1 interaction, and the two mutations within the homeodomain region are essential for specific Six1-DNA binding. Identification of SIX1 mutations as causing BOR/BO offers insights into the molecular basis of otic and renal developmental diseases in humans.
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Rainer G
authors.initials: RG
authors.lastname: Ruf
authors.forename: Pin-Xian
authors.initials: PX
authors.lastname: Xu
authors.forename: Derek
authors.initials: D
authors.lastname: Silvius
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.forename: Frank
authors.initials: F
authors.lastname: Beekmann
authors.forename: Ulla T
authors.initials: UT
authors.lastname: Muerb
authors.forename: Shrawan
authors.initials: S
authors.lastname: Kumar
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Neuhaus
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Kemper
authors.forename: Richard M
authors.initials: RM
authors.lastname: Raymond
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Brophy
authors.forename: Jennifer
authors.initials: J
authors.lastname: Berkman
authors.forename: Michael
authors.initials: M
authors.lastname: Gattas
authors.forename: Valentine
authors.initials: V
authors.lastname: Hyland
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Ruf
authors.forename: Charles
authors.initials: C
authors.lastname: Schwartz
authors.forename: Eugene H
authors.initials: EH
authors.lastname: Chang
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.forename: Dominique
authors.initials: D
authors.lastname: Weil
authors.forename: Christine
authors.initials: C
authors.lastname: Petit
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D019280:Branchio-Oto-Renal Syndrome / Q000235:genetics*; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter / Q000235:genetics; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D009687:Nuclear Proteins; C099236:SIX1 protein, human; D015534:Trans-Activators; D004247:DNA; C104381:EYA1 protein, human; D017027:Protein Tyrosine Phosphatases