EYA1 – Branchio-oto-renal Syndrome

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial arch anomalies, preauricular pits, external ear malformations, hearing impairment, and renal anomalies (PMID:9777487). The disease is caused by heterozygous mutations in the human EYA1 gene, which encodes a transcriptional coactivator and protein-tyrosine phosphatase critical for branchial, otic, and renal development.

Several case series have reported over 200 affected probands across more than 80 unrelated families, demonstrating autosomal dominant inheritance with frequent de novo and familial segregation of loss-of-function variants ([PMID:9361030]). In a Japanese family, the nonsense variant c.678C>G (p.Tyr226Ter) segregated with disease across three generations ([PMID:10429368]). A Danish pedigree with five affected individuals in three generations harbored a novel splice-site mutation IVS9+1G>C, consistent with haploinsufficiency ([PMID:15684871]).

Functional studies indicate that BOR-associated EYA1 mutations disrupt normal EYA1 splicing, decrease nuclear localization, and impair protein-protein interactions with SIX transcription factors. Mammalian two-hybrid and GST-pulldown assays revealed that mutations such as p.Ser487Pro and p.Gly426Ser abrogate interactions with SIX1, DACH1, and G proteins, reducing transcriptional activation of downstream targets ([PMID:11950062]). In Xenopus laevis, expression of human BOR variants (p.Gly426Ser, p.Arg440Gln) led to defective otic vesicle development and altered expression of neural crest and otic genes, supporting a dominant-negative mechanism ([PMID:19951260]).

No studies to date have refuted the role of EYA1 in BOR syndrome. The consistent identification of truncating, splice-site, and missense variants in the conserved EYA domain across diverse populations, combined with robust functional concordance, supports a definitive gene-disease relationship.

Key Take-home: EYA1 haploinsufficiency is a definitive cause of autosomal dominant BOR syndrome; genetic testing of EYA1—including sequencing and copy-number analysis—is essential for accurate diagnosis, guiding clinical management and genetic counseling.

References

• Human molecular genetics • 1997 • Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1. PMID:9361030
• Journal of human genetics • 1999 • EYA1 nonsense mutation in a Japanese branchio-oto-renal syndrome family. PMID:10429368
• Genetic testing • 2004 • Identification of a novel EYA1 splice-site mutation in a Danish branchio-oto-renal syndrome family. PMID:15684871
• Journal of human genetics • 2002 • Impaired interactions between mouse Eya1 harboring mutations found in patients with branchio-oto-renal syndrome and Six, Dach, and G proteins. PMID:11950062
• Biology of the cell • 2010 • EYA1 mutations associated with the branchio-oto-renal syndrome result in defective otic development in Xenopus laevis. PMID:19951260
• Journal of communication disorders • 1998 • Branchio-oto-renal syndrome. PMID:9777487

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