This report describes branchiootorenal spectrum disorders (BOR/BOS), EYA1-related, which exhibit autosomal dominant inheritance. The human gene implicated in this disease is EYA1, which acts a protein phosphatase and as a transcriptional coactivator, and which is involved in multiple processes including embryonic organogenesis and DNA repair. Specific diseases within the branchiootorenal spectrum associated with EYA1 include branchiootorenal syndrome 1 (FBhh0000464) and branchiootic syndrome 1 (FBhh0000465). There is a single fly ortholog, Dmel\eya, for which for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\eya is also orthologous to three additional human genes, EYA2, EYA3, and EYA4. EYA4 has been implicated in two diseases, a form of deafness (MIM:601316) and a form of dilated cardiomyopathy (MIM:605362).
The human EYA1 gene has not been introduced into Drosophila, however, several orthologous genes from mouse, Mmus\Eya1, Mmus\Eya2, and Mmus\Eya3 have been introduced into flies. Partial heterologous rescue (functional complementation) is observed for all three mouse genes, tested against a hypomorphic allele of Dmel\eya.
Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G594S in the fly eya gene (corresponds to G393S(G426S) in the human EYA1 gene), S655P in the fly eya gene (corresponds to S454P(S487P) in the human EYA1 gene), L673R in the fly eya gene (corresponds to L472R(L505R) in the human EYA1 gene). It has been postulated that in humans the following two variants are associated with anterior segment anomalies manifesting in ocular disorders, but supporting evidence is limited: E528K in the fly eya gene (corresponds to E330K(E363K) in the human EYA1 gene), R715G in the fly eya gene (corresponds to R514G(R547G) in the human EYA1 gene).
Severe loss-of-function mutations of Dmel\eya are lethal in the embryonic stage. Animals homozygous for the original weaker allele survive to adulthood, but lack eyes, due to the failure of the eye discs to differentiate. Ectopic expression of eya induces ectopic formation of eye tissue. The variable phenotypes produced across the range of eya activity have been used to characterize variants analogous to those implicated in branchiootorenal spectrum disorders. Genetic and physical interactions of Dmel\eya have been described; see below and in the gene report for eya.
[updated Jan. 2017 by FlyBase; FBrf0222196]
Branchiootorenal (BOR) syndrome is characterized by malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment, branchial fistulae and cysts, and renal malformations ranging from mild renal hypoplasia to bilateral renal agenesis. Some individuals progress to end-stage renal disease later in life. Branchiootic syndrome (BOS) has the same features as BOR syndrome but without renal involvement. [from Gene Reviews, Branchiootorenal Spectrum Disorders; pubmed:20301554]
The phenotypic manifestations of branchiootorenal spectrum disorders are typically in the areas of the branchial arch, ear and kidney. For the implicated gene EYA1, some missense mutations may result in ocular defects (Azuma et al., 2000; pubmed:10655545).
Molecular genetic testing of EYA1 detects pathogenic variants in approximately 40% of individuals with the clinical diagnosis of BOR/BOS. [from Gene Reviews, Branchiootorenal Spectrum Disorders; pubmed:20301554]
The EYA1 protein functions both as a protein phosphatase and as a transcriptional coactivator; it promotes efficient DNA repair; it is required for normal embryonic development. [from Gene Cards, EYA1; 2017.01.06]
Many to one: 4 human to 1 Drosophila; the other human genes are EYA2, EYA3, and EYA4.
Moderate- to high-scoring ortholog of human EYA1, EYA2, EYA3, and EYA4 (1 Drosophila to 4 human). Dmel\eya shares 39-45% identity and 51-58% similarity with the human genes.
