Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome

Bethan E. Hoskins, Carl H. Cramer, Derek Silvius, Dan Zou, Richard M. Raymond, Dana J. Orten, William J. Kimberling, Richard J.H. Smith, Dominique Weil, Christine Petit, Edgar A. Otto, Pin Xian Xu, Friedhelm Hildebrandt

    Research output: Contribution to journalArticlepeer-review

    163 Scopus citations


    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.

    Original languageEnglish (US)
    Pages (from-to)800-804
    Number of pages5
    JournalAmerican Journal of Human Genetics
    Issue number4
    StatePublished - Apr 2007

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)


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