Genetic Profiling of Variants in CYPIBI Gene in Families with Primary Congenital Glaucoma

Abstract

Glaucoma is an optic neuropathy characterized by distinctive damage to the optic nerve. Primary congenital glaucoma (PCG) is a rare autosomal recessive condition characterized by abnormally high intraocular pressure leading to optic nerve damage and blindness if not timely diagnosed and managed. The PCG is attributed to mutations in the cytochrome P4501B1 (CYP1B1) gene. This study focused on elucidating the genetic basis of PCG in three families, which were recruited from different areas of Pakistan. The patients displayed glaucomatous eyes, photophobia, corneal opacity, and epiphora, which are characteristic signs associated with PCG. For this purpose, coding exons 2 and 3 of CYP1B1 were screened in proband of three families. Sequencing identified two variants including c.1347 T>C and c.1330 C>T in family B and C. In silico analysis with mutation taster, Franklin, HSF, and PAHTHER-HMM showed the pathogenic nature of c.1330 C>T variant only. This variant is designated as a null variant (Stop gain) and is anticipated to undergo nonsense-mediated decay (NMD) due to the premature stop codon. The escape NMD can produce a truncated protein, which lacks the C-terminal part (15% of total protein). 3D structural analysis also revealed that truncated protein has a missing L helix and heme binding regions which are critical components for enzyme activity. Therefore, it can be concluded that mutation c.1330 C>T (Arg444X) is responsible for PCG phenotype in the affected members of families B and C. In family A disease-causing mutation could not be identified in the CYP1B1 gene and may require the sequencing of other known PCG genes. Keywords: Primary Congenital glaucoma, R444*, CYP1B1