Branchio-oto-renal syndrome: comprehensive review based on nationwide surveillance in Japan.

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Abstract

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchiogenic malformation, hearing loss and renal anomalies. The prevalence of BOR syndrome is 1/40,000 in Western countries, and nationwide surveillance in 2009-2010 identified approximately 250 BOR patients in Japan. Three causative genes for BOR syndrome have been reported thus far: EYA1, SIX1, and SIX5, but the causative genes for approximately half of all BOR patients remain unknown. This review article discusses the epidemiology, clinical symptoms, genetic background and management of BOR syndrome.

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Most cited references 34

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A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family.

S Abdelhak, V Kalatzis, R Heilig … (1997)

A candidate gene for Branchio-Oto-Renal (BOR) syndrome was identified at chromosome 8q13.3 by positional cloning and shown to underlie the disease. This gene is a human homologue of the Drosophila eyes absent gene (eya), and was therefore called EYA1. A highly conserved 271-amino acid C-terminal region was also found in the products of two other human genes (EYA2 and EYA3), demonstrating the existence of a novel gene family. The expression pattern of the murine EYA1 orthologue, Eya1, suggests a role in the development of all components of the inner ear, from the emergence of the otic placode. In the developing kidney, the expression pattern is indicative of a role for Eya1 in the metanephric cells surrounding the 'just-divided' ureteric branches.

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The Eyes Absent proteins in development and disease.

Nagendra Hegde, Emmanuel Tadjuidje (2013)

The Eyes Absent (EYA) proteins, first described in the context of fly eye development, are now implicated in processes as disparate as organ development, innate immunity, DNA damage repair, photoperiodism, angiogenesis, and cancer metastasis. These functions are associated with an unusual combination of biochemical activities: tyrosine phosphatase and threonine phosphatase activities in separate domains, and transactivation potential when associated with a DNA-binding partner. EYA mutations are linked to multiorgan developmental disorders, as well as to adult diseases ranging from dilated cardiomyopathy to late-onset sensorineural hearing loss. With the growing understanding of EYA biochemical and cellular activity, biological function, and association with disease, comes the possibility that the EYA proteins are amenable to the design of targeted therapeutics. The availability of structural information, direct links to disease states, available animal models, and the fact that they utilize unconventional reaction mechanisms that could allow specificity, suggest that EYAs are well-positioned for drug discovery efforts. This review provides a summary of EYA structure, activity, and function, as they relate to development and disease, with particular emphasis on recent findings.

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Cooperation of six and eya in activation of their target genes through nuclear translocation of Eya.

H Ohto, S Kamada, K Tago … (1999)

Drosophila sine oculis and eyes absent genes synergize in compound-eye formation. The murine homologues of these genes, Six and Eya, respectively, show overlapping expression patterns during development. We hypothesized that Six and Eya proteins cooperate to regulate their target genes. Cotransfection assays were performed with various combinations of Six and Eya to assess their effects on a potential natural target, myogenin promoter, and on a synthetic promoter, the thymidine kinase gene promoter fused to multimerized Six4 binding sites. A clear synergistic activation of these promoters was observed in certain combinations of Six and Eya. To investigate the molecular basis for the cooperation, we first examined the intracellular distribution of Six and Eya proteins in transfected COS7 cells. Coexpression of Six2, Six4, or Six5 induced nuclear translocation of Eya1, Eya2, and Eya3, which were otherwise distributed in the cytoplasm. In contrast, coexpression of Six3 did not result in nuclear localization of any Eya proteins. Six and Eya proteins were coimmunoprecipitated from nuclear extracts prepared from cotransfected COS7 cells and from rat liver. Six domain and homeodomain, two evolutionarily conserved domains among various Six proteins, were necessary and sufficient for the nuclear translocation of Eya. In contrast, the Eya domain, a conserved domain among Eya proteins, was not sufficient for the translocation. A specific interaction between the Six domain and homeodomain of Six4 and Eya2 was observed by yeast two-hybrid analysis. Our results suggest that transcription regulation of certain target genes by Six proteins requires cooperative interaction with Eya proteins: complex formation through direct interaction and nuclear translocation of Eya proteins. This implies that the synergistic action of Six and Eya is conserved in the mouse and is mediated through cooperative activation of their target genes.