In Search of Novel Genes in Branchio‐oto‐renal Spectrum Disorders

Several members of the Six family of transcription factors play important roles in vertebrate craniofacial development. Six1 is particularly important for the development of the cranial sensory organs including the inner ear. Mutations in either Six1 and one co‐factor gene, Eya1 , result in human Branchiootorenal spectrum disorders that have mild craniofacial defects and hearing loss. However, these mutations only account for about half of the patients, indicating that other mutations underlie this spectrum. To discover potential new causative genes, we identified over 30 Xenopus genes with high sequence identity to proteins previously shown to interact with Drosophila Six, and we determined that many of these genes are expressed in the otocyst, the precursor of the inner ear. We now show that 4 of the novel candidate co‐factors biochemically interact with Six1 and thus may modify its transcriptional activity. When the endogenous expression level of each of these candidate co‐factors is reduced, there is a loss of otic placode genes and expansion of neural plate genes. When the endogenous expression level of each of these candidate co‐factors in increased, Six1 expression is reduced. These results suggest that these previously uncharacterized Six‐interacting partners have potential important roles in vertebrate craniofacial development and congenital syndromes. Support or Funding Information NIH R01 DE022065