Human Albinism and Animal Models of Albinism

Ten phenotypic forms of oculocutaneous albinism (OCA) and four forms of ocular albinism (OA) have been identified in man. All have optic neuronal decussation defects at the optic chiasm. Thus any proposed animal model for these disorders must share optic neuronal decussation defects in addition to hypopigmentation. Three, tyrosinase-negative (ty-neg), yellow mutant (ym), and platinum (pt), OCA appear to be allelic in humans. Two, ty-neg and pt, OCA appear to be analogous to c-locus mutants c/c and c^p/c^p in mice, but no homologue is known in mice for ym OCA. Tyrosinase-positive (ty-pos) OCA, which is nonallelic with ty-neg OCA, shares many morphological and biochemical features with pink-eyed mice. Chediak-Higashi syndrome (CHS) and Hermansky-Pudlak syndrome (HPS) appear to be due to genes acting extrinsic to the melanin pathway. CHS is homologous with beige in mice. HPS was investigated in northwestern Puerto Rico, where it affects approximately 1 in 2,000 persons. Approximately 68% of 37 deceased HPS patients died from sequelae of ceroid storage disease, restrictive lung disease between ages 35 and 46 years (43%), and granulomatous colitis (8%) or hemorrhage (16%). The most accurate and consistent diagnostic feature of HPS is lack of platelet dense bodies. HPS patients with ceroid storage disease had high urinary levels of long-chain isoprenoid alcohols, dolichols, similar to that seen in the neuronal-ceroid lipofuscinoses (Batten disease). Dolichols are constituents of lysosomes, and their elevation in HPS suggests that this syndrome carries a lysosomal defect. There is no degradative pathway for ceroid and dolichols, which are eliminated by exocytosis. The exocytic process is thought to involve a thioendoproteinase. Pale-ear mice have been proposed as a model for HPS; their platelets lack dense bodies, and they are depigmented. Leupeptin, a thioendoproteinase inhibitor, administered to 100-day-old pale-eared and black wild-type C57 mice for 10 days resulted in the accumulation of ceroid in tissues in the same pattern as that in HPS, but granulomas of gut or fibrosis of lungs were not seen. Determinations of homology between mice and men at the molecular level is now possible with the isolation of mouse tyrosinase by Yamamoto et al. and isolation by Kwon et al. of human tyrosinase mapping at the c-locus in mice.