Identifying new genes for branchio-oto-renal syndrome

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DESCRIPTION (provided by applicant): Identification of new genes for branchio-oto-renal syndrome. Branchio-oto-renal syndrome (BOR) is an autosomal dominant developmental disorder characterized by the association of hearing loss, renal anomalies, and branchial arch defects. Branchio-otic syndrome (BO) is a related disorder without renal anomalies. Dominant mutations in the human ortholog of the Drosophila eyes absent gene (EYA1) cause BOR and BO. By total genome search for linkage in a large kindred of 18 individuals affected with BO, we mapped a new gene locus (BOS3) to chromosome 14q21. Within the 33 Mb critical genetic interval we located the SIX1 gene, which is known to play a role in the PAX-EYA-SIX hierarchy of developmental regulation in the organogenesis of kidney and ear. By direct sequencing we identified 3 different SIX1 mutations in this kindred and in 2 additional kindred with BOR/BO, thus identifying SIX1 as a new gene causing BOR and BO. By functional analysis we show that all 3 mutations interfere with Eya1-Six1 protein-protein interaction, and that the two homeodomain mutations impede Six1-DNA binding. In addition, we generated first evidence that SOX13 mutations may be found in patients with BOR/BO. The C. elegans INTERACTOME project recently confirmed eya-1/six-1 interaction and identified in this model organism many further eya-1 interaction partners, the human orthologs of which represent excellent candidate genes for BOR/BO. This proposal is aimed at the identification of further genes, mutations in which cause BOR/BO and at the functional characterization of SIX1, SOX13, and related genes within the context of BOR/BO and kidney and ear development in humans. Specifically, we propose to: 1) Detect further mutations in the newly identified BOR/BO genes SIX1 and SOX13, and study their functional role for kidney and ear developmental defects in BOR/BO. 2) Identify further genes as responsible for BOR/BO, using as candidate genes members of the Eya1/Six1 transcriptional complex and eya-1 binding partners derived from the C. elegans INTERACTOME data, and study genotype/phenotype relationships. 3) Identify a new gene causing BO by positional cloning in a new large BOR/BO kindred. Identification of new genes causing branchio-oto-renal syndrome will offer new insights into the pathomechanisms of hearing defects, urinary tract malformations as well as kidney and ear development.