The ATOH c.1030delC mutation causes a frameshift that alters the last ten residues of the normally 354-amino acid protein and adds six residues to its length before a stop. Western blot analysis of wild-type and mutant ATOH1 proteins revealed a significantly slower rate of degradation for mutant compared to the wild-type protein. In mice, the naturally occurring mutation Atoh1 p.Met200Ile causes hearing loss, progressive cerebellar atrophy, and trembling. Another mouse with a mutation at the phosphorylation site Atoh1 S193 was shown to have late-onset deafness. We hypothe that the human ATOH1 mutation increases the stability of the protein through decreased degradation, resulting in increased enhancement of its own expression. This untimely expression may generate immature ectopic hair cells that interfere with development of normal hair cells.
ATOH1