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

Department of Pediatrics and of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 05/2007; 80(4):800-4. DOI: 10.1086/513322
Source: PubMed

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.

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Available from: Dana Orten, Jun 04, 2014
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    • "Six1, Six2, and Six5 are all expressed in the developing kidney (Ohto et al., 1998). Mutations in SIX1 (Ruf et al., 2004) and SIX5 (Hoskins et al., 2007) genes in humans have been associated to the branchio-oto-renal (BOR) syndrome, which is characterized by renal hypodysplasia, cervical fistulae, and ear anomalies (Vervoort et al., 2002; Weber et al., 2008a). This syndrome is most frequently associated to mutations in the EYA1 gene, an ortholog of Drosophila eye. "
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    Birth Defects Research Part C Embryo Today Reviews 11/2014; 102(4). DOI:10.1002/bdrc.21084
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    • "could underlie the manifestations seen in our pedigree. In addition, paralogs of EYA and SIX are ideal candidates for mutation screening as genes with overlapping functions and expression patterns or gene products that interact with each other could lead to the development of similar disease phenotypes [Hoskins et al., 2007]. "
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    • "All exons and flanking intronic sequences of EYA1, SIX1, and SIX5 were sequenced as previously described [Hoskins et al., 2007; Ruf et al., 2004]. "
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