Inner Ear and Kidney Anomalies Caused by IAP Insertion in an Intron of the Eya1 Gene in a Mouse Model of BOR Syndrome

• Published in: Human molecular genetics 1999-04, Vol.8 (4), p.645-653
• Main Authors: Johnson, Kenneth R., Cook, Susan A., Erway, Lawrence C., Matthews, Angela N., Sanford, L. Phillip, Paradies, Nancy E., Friedman, Rick A.
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Behavior, Animal; Biological and medical sciences; Blotting, Northern; Branchio-Oto-Renal Syndrome - genetics; Branchio-Oto-Renal Syndrome - pathology; Chromosome Mapping; Classical genetics, quantitative genetics, hybrids; Cochlea - abnormalities; Crosses, Genetic; Deafness - genetics; Deafness - pathology; Disease Models, Animal; DNA Mutational Analysis; Ear, auditive nerve, cochleovestibular tract, facial nerve: diseases, semeiology; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Genes, Intracisternal A-Particle; Genetics of eukaryotes. Biological and molecular evolution; Intracellular Signaling Peptides and Proteins; Introns - genetics; Kidney - abnormalities; Male; Medical sciences; Mice; Mice, Inbred C3H; Molecular Sequence Data; Mutagenesis, Insertional; Non tumoral diseases; Nuclear Proteins; Otorhinolaryngology. Stomatology; Protein Tyrosine Phosphatases; RNA - genetics; RNA - metabolism; Tissue Distribution; Trans-Activators - genetics; Vertebrata
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/8.4.645

A spontaneous mutation causing deafness and circling behavior was discovered in a C3H/HeJ colony of mice at the Jackson Laboratory. Pathological analysis of mutant mice revealed gross morphological abnormalities of the inner ear, and also dysmorphic or missing kidneys. The deafness and abnormal behavior 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) syndrome, an autosomal dominant disorder characterized by hearing loss with associated 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 with reduced expression of the normal Eya1 message and formation of additional aberrant transcripts. The hypomorphic nature of the mutation may explain its recessive inheritance, if protein levels in homozygotes, but not heterozygotes, are below a critical threshold needed for normal developmental function. The new mouse mutation is designated Eya1bor to denote its similarity to human BOR syndrome, and will provide a valuable model for studying mutant gene expression and etiology.