Oculocutaneous Albinism Type 1: The Last 100 Years WILLIAM S. OETTING, JAMES P. FRYER, SABITHA SHRIRAM and RICHARD A. KING Department of Medicine, and Institute of Human Genetics, University of Minnesota, Minneapolis, MN, USA *Address reprint requests to William S. Oetting Ph.D., Department of Medicine, Mayo Mail Code 485, 420 Delaware St. S.E., University of Minnesota, Minneapolis, MN 55455, USA. E-mail: bill@lenti.med.umn.edu Received 3 February 2003; in final form 3 March 2003 Research on human albinism has been central to many of the major discoveries in human genetics. These include the first evidence that Mendel’s rules of genetic segregation apply to humans,firstpublishedin1903.Contrarytoinitialthoughtthat albinismiscausedbymutationsinasinglegene,wenowknow that the genetics of albinism are complex. The complexity of albinism was hinted at, in early publications, but has only recently been fully appreciated with the advent of molecular techniques. Currently, 12 different genes have been identified, that when mutated, result in a different type of albinism. Oculocutaneous albinism type 1 (OCA1), resulting from mutations of the tyrosinase gene, is genetically and biochem- icallythebestunderstoodtypeofalbinism.Thoughmuchofthe research in albinism has involved OCA1, there are many unanswered questions about OCA1 and albinism, in general. The next 100 yr should still provide many surprises as did the first 100 yr. Key words: Oculocutaneous albinism, Tyrosinase gene, Ocu- locutaneous albinism type 1 (OCA1) INTRODUCTION Research on albinism has been instrumental in helping us understand human genetic diseases. Because of its obvious phenotype, albinism is one of the earliest genetic disorders to be studied. Clinically, albinism is associated with a reduction ofmelaninpigmentintheskin,hairandeyes(1).Areduction of melanin in the eyes is associated with several ocular abnormalities including foveal hypoplasia and the resulting decrease of visual acuity, misrouting of the optic nerve fibres from the retina to the visual cortex, nystagmus, strabismus and iris translucency (2). Although originally thought to be a simple single gene disorder, current research has shown that albinism is a complex disorder. There are two major forms of albinism, oculocutaneous albinism (OCA) with involvement of the skin, hair and eyes, and ocular albinism (OA) with involvement primarily of the eyes. Oculocutaneous albinism has been shown to be associated with several genes (see Table 1). Ocular albinism (X-linked; Nettelship–Falls) has been linked to a single gene, OA1 (3). This review will focus on OCA1, caused by mutations of the tyrosinase gene. The Genetics of Albinism Analysis of the segregation patterns of albinism in mice first indicated that Mendel’s laws of segregation applied to mammals and not just plants (4). Farabee, in 1903, was the first to suggest that albinism in humans could also be considered a recessive genetic trait, as was previously shown in mice (5). This conclusion was further amplified in a response by W. E. Castle following Farabee’s note stating, ÔIn the case of negro albinism observed by Mr Farabee, the result is throughout a Mendelian one, on the hypothesis that albinism is recessiveÕ (6). In a six-volume monograph by Pearson, Nettleship and Usher, published between 1911 and 1913, over 650 pedigrees containing individuals with ÔalbinismÕ, were analysed (7). Pearson wrote of variation in the level of pigmentation associated with albinism, but attributed this variation to a gradual transition of albinism from complete to incomplete to partial albinism (he included Waardenburg syndrome and piebaldism as part of a single continuum). Pearson was not convinced of the Mendelian nature of albinism and stated ÔIf such a definition be needful to test any special theory of inheritance, then it is, we think, clear that albinism in man Abbreviations – OCA, oculocutaneous albinism; SNP, single nucleotide polymorphism PIGMENT CELL RES 16: 307–311. 2003 Copyright Ó Blackwell Munksgaard 2003 Printed in UK—all rights reserved ISSN 0893-5785 Pigment Cell Res. 16, 2003 307