Mutation analysis and molecular dynamics of TYR gene in Oculocutaneous albinism: L-tyrosine binding and therapy

Oculocutaneous albinism (OCA) is a rare, autosomal recessive disorder of melanin biosynthesis characterized by reduced or absent pigment granules in the hair, skin and eyes. The present study assesses the genetic etiology of OCA in Pakistani families from the district of Charsadda, identifying a missense mutation (c. 1255 G>A) in exon 4 of TYR gene and splicing error in the Group-2. The mutation, predicted to be pathogenic by using PolyPhen-2, substitutes glycine with arginine impairing protein’s function. Docking and dynamic simulations of L-tyrosine with both modified and unmodified TYR proteins imply that L-tyrosine is not defective in binding to the TYR protein altogether, but the perturbations in the binding dynamics observed in this variant lead to lack of melanin synthesis, with consequences in the OCA phenotype. The findings of this study suggest that L-tyrosine supplementation, though could not cure OCA, helps improve pigmentation and neurotransmitter synthesis, potentially controlling some OCA symptoms.