Detection of Mutations in the Tyrosinase Gene in a Patient with Type IA Oculocutaneous Albinism

Abstract

OCULOCUTANEOUS albinism is a group of severe genetic disorders of pigmentation characterized by reduced or absent biosynthesis of melanin pigment in the melanocytes of the skin, hair follicle, and eye.¹ Because of the striking phenotype, oculocutaneous albinism was one of the first genetic disorders recognized, and its typical clinical features,^{2 , 3} autosomal recessive mode of inheritance, and genetic heterogeneity^{2 3 4} are apparent even in classical descriptions. In the classic, most severe form of oculocutaneous albinism, Type IA, the lack of melanin biosynthesis results from the absence of activity of the enzyme tyrosinase (monophenol monooxygenase; EC 1.14.18.1) in pigment cells. Tyrosinase is a copper-containing enzyme that catalyzes both the oxidation of tyrosine to dopa and the subsequent dehydrogenation of dopa to dopaquinone.⁵ Deficiency in the activity of tyrosinase in the skin of albino animals was first demonstrated in 1904,⁶ and as early as 1908 Garrod suggested that albinism might be an inborn error of metabolism.⁷ The recent cloning of complementary DNAs (cDNAs) encoding normal human tyrosinase^{8 9 10} has made possible the direct characterization of the mutations in the tyrosinase gene responsible for deficient tyrosinase activity in Type IA oculocutaneous albinism. We determined the sequence of the tyrosinase coding region in DNA from a woman with classic, severe Type IA oculocutaneous albinism. We found two different missense mutations, one inherited from each parent, that result in amino acid substitutions within one of the two putative copper-binding sites.