Rare mutations in Atoh1 lead to hearing loss

Abstract Background Atoh1 has a pivotal effect on hair cell differentiation and viability. Due to the essential role of this gene in the development and differentiation of inner ear hair cells, this study investigated the mutations in the Atoh1 (also known as Hath1 in humans) gene. Methods In this study, 40 families with deafness living in Chaharmahal va Bakhtiari, Isfahan, and Khuzestan provinces were selected from genetic clinics in Iran. The genomic DNA was extracted from the blood samples of 40 deaf patients, and the Atoh1 gene was studied by PCR amplification followed by sequencing. A High-Resolution Melting Analysis (HRM) method was established to evaluate the melting point of natural and mutant PCR products. The observed allelic changes in the Atoh1 gene were further analyzed in-silico. The ATOH1 protein structure and function were analyzed by Gromax software. Results HRM method revealed a higher melting point for a mutant PCR product compared to the natural sequence; this clear difference could help further rapid, easy, and low-cost detection in other samples. This mutant sample belonged to a patient with syndromic hearing loss who exhibited two missense mutations (c.605A>G and c.397G>A) in the Atoh1 gene. Possible structural and functional outcomes due to the mutation on the ATOH1 protein were predicted and explained by molecular dynamics simulation methods using Gromax software. Conclusion Because of the vital developmental roles, mutations in the ATOH1 gene are mostly lethal and rare. The observation of tolerable mutations in this protein may open doors for a better physiological understanding of the importance of different motifs in this protein.