Abstract
AIM: To detect and segregate causative mutations in congenital families with optic nerve hypoplasia (ONH). METHODS: Two unrelated consanguineous Pakistani families with severe ONH, showing features of micropthalmia, nystagmus, corneal opacity, and keratopathy were included. Genetic analysis was carried out by Target Panel Sequencing, and the nucleotide variant was confirmed by Sanger sequencing. In silico analyses were carried out to study the protein order-disorder functions and their effects on messenger ribonucleic acid (mRNA). RESULTS: Target panel sequencing revealed that the afflicted family members carried a novel frameshift mutation (NM_145178.4; c.91del G; p.Gly31Glyfs*55) that ensued in the conservation of an amino acid residue in the bHLH domain of ATOH7 protein. In silico studies predicted that the activity of the ATOH7 gene is probably affected by this mutation, which results in a shortened and non-functional protein. Three-dimensional structural analysis shows that DNA binding may be impacted by amino acid changes from non-polar to positively charged and vice versa (Arg42Pro and Pro18Arg), as well as from positively charged (Arg) to a small polar amino acid (Gly). CONCLUSION: A novel ATOH7 mutation is harmful. This study also emphasizes the potential effects of modified ATOH7 configurations on the stability and functionality of proteins.