Identification and structural analysis of pathogenic variants in MYOC and CYP1B1 genes in Indian JOAG patients.

Purpose: Juvenile onset open-angle glaucoma (JOAG) manifests in individuals under the age of 40, resulting in elevated intraocular pressure and significant optic nerve damage. To broaden the spectrum of mutations associated with JOAG and to determine their specific structural implications, we examined Myocilin and Cytochrome P450 1B1 gene in a cohort of 111 unrelated North Indian patients diagnosed with JOAG.

Study design: A clinical and experimental study.

Methods: PCR-DNA sequencing screened the coding exons and intron-exon junctions of the MYOC and CYP1B1 genes in 111 unrelated JOAG patients and 100 controls. Identified sequence variations were searched in the ClinVar database, HGMD, and dbSNP. Six different online available algorithms including rare exome variant ensemble learner (REVEL), Sorting Intolerant From Tolerant (SIFT), Mutation Taster, SNAP2, IMutant2.0, and MutPred2 were used for the pathogenicity prediction of missense variations. The Structural consequences of detected possible pathogenic variations were predicted by using PyMol, Chimera and MD simulation of these changes.

Results: Potentially-pathogenic variations were observed in thirty patients (27.02%) within the MYOC and CYP1B1 genes, encompassing both novel and previously documented variants. Structural predictions of novel potentially-pathogenic mutations indicate altered stability and flexibility.

Conclusion: Analysis reveals a higher prevalence of CYP1B1 gene variants (22.5%) relative to MYOC gene variants (4.5%), suggesting that CYP1B1 is the predominant gene implicated in JOAG among Indian patients. Our findings enhance the understanding of mutation spectra and frequencies of MYOC and CYP1B1gene in JOAG among the North Indian population. Structural predictions of novel pathogenic mutations could enhance the understanding of JOAG pathogenesis and support subsequent functional analysis.