Mutations of the
tyrosinase gene are responsible for type I (
tyrosinase-related)
oculocutaneous albinism (OCA), an autosomal recessive genetic syndrome with a broad phenotypic spectrum. Mutant
tyrosinase alleles can be associated with no
melanin synthesis (I-A,
tyrosinase-negative OCA), small to moderate amounts of
melanin (I-B, yellow OCA) or unusual pigment patterns (I-TS, temperature-sensitive OCA). A total of 26 mutations of this gene have been described in type I OCA. Analysis of all known mis-sense mutations (n = 17) shows that most cluster in three areas of the coding region. Two clusters involve the
copper A or
copper B binding sites and may disrupt the
metal ion-
protein interaction necessary for
enzyme function and the third cluster is located in exon I. Computer modeling of the secondary structure of the
copper binding regions based on homology with the known crystal structure of
hemocyanin show that they both consist of two alpha helices containing three
histidine ligands that complex to a single
copper atom. Mutations in the
copper B binding region lie in the region between the two alpha helices that consists of a loop structure. These mutations may affect
tyrosinase activity by either altering the position of the alpha helical domains and thus preventing proper
copper binding to the
histidine ligands, or affecting a catalytic or substrate binding site located between the two alpha helical domains.