Transcription Factor SIX5 Is Mutated in Patients with Branchio-Oto-Renal Syndrome

• Published in: American journal of human genetics 2007-04, Vol.80 (4), p.800-804
• Main Authors: Hoskins, Bethan E., Cramer, Carl H., Silvius, Derek, Zou, Dan, Raymond, Richard M., Orten, Dana J., Kimberling, William J., Smith, Richard J.H., Weil, Dominique, Petit, Christine, Otto, Edgar A., Xu, Pin-Xian, Hildebrandt, Friedhelm
• Format: Article
• Language: English
• Subjects: Base Sequence; Biological and medical sciences; Branchio-Oto-Renal Syndrome - genetics; Caenorhabditis elegans; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic Predisposition to Disease; Genetic Testing; Genetics of eukaryotes. Biological and molecular evolution; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Luciferases; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Mutation, Missense - genetics; Nuclear Proteins - metabolism; Protein Tyrosine Phosphatases - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/513322

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.