Inner ear and kidney anomalies caused by IAP insertion in an intron of theEya1 gene in a mouse model of BOR syndrome

A spontaneous mutation causing deafness and circling behavior was discovere d in a C3H/HeJ colony of mice at the Jackson Laboratory. Pathological analy sis of mutant mice revealed gross morphological abnormalities of the inner ear, and also dysmorphic or missing kidneys. The deafness and abnormal beha vior were shown to be inherited as an autosomal recessive trait and mapped to mouse chromosome 1 near the position of the Eya1 gene. The human homolog of this gene, EYA1, has been shown to underly branchio-oto-renal (BOR) syn drome, an autosomal dominant disorder characterized by hearing loss with as sociated branchial and renal anomalies. Molecular analysis of the Eya1 gene in mutant mice revealed the insertion of an intracisternal A particle (IAP ) element in intron 7, The presence of the IAP insertion was associated wit h reduced expression of the normal Eya1 message and formation of additional aberrant transcripts. The hypomorphic nature of the mutation may explain i ts recessive inheritance, if protein levels in homozygotes, but not heteroz ygotes, are below a critical threshold needed for normal developmental func tion. The new mouse mutation is designated Eya1(bor) to denote its similari ty to human BOR syndrome, and will provide a valuable model for studying mu tant gene expression and etiology.