Molecular Characterization of Oculocutaneous Albinism in Consanguineous Pakistani Families: Unraveling Disease-Causing Pathogenic Variants in OCA2 and TYR Genes for Precision Diagnosis.

Oculocutaneous albinism is a rare genetic disorder characterized by the absence or reduction of melanin pigment in the skin, hair, and eyes, leading to various visual and dermatological challenges. To shed light on the molecular pathology of OCA in consanguineous Pakistani families, we conducted whole-exome sequencing on affected individuals from two families. We identified disease-causing homozygous mutations in the TYR (NM_000372) and OCA2 (NM_000275.3) genes that segregated within their respective pedigrees. In family AL01, we identified a novel mutation in the TYR gene, resulting in a missense change, c.1280T>C, leading to p.V427A. In family AL02, we detected a splice site variant, c.1045-15T>G in OCA2 gene. Protein model of the V427A mutation within the tyrosinase protein predicted that as the mutant amino acid was considerably smaller in size than the wild type, it might have created a potential gap in protein's core structure. The V427A mutation is positioned centrally within the Lumenal melanosome repeat domain raises concerns about potential structural alterations in this domain due to disparities between the wild-type and mutant residue, potentially leading to a loss of function in this repeated region. Our study provides a deeper understanding of the molecular basis of OCA in consanguineous Pakistani families by identifying disease-causing mutations in the TYR and OCA2 genes. The novel TYR mutation, V427A, offers insights on the structural consequences of this mutation, which could have implications for understanding the pathology of OCA and potentially effecting future diagnostic and therapeutic approaches for individuals affected by this rare genetic disorder.