Harlequin mice exhibit paucity of fur resulting in near baldness in hemizygous males and homozygous females. Heterozygous females have a patchy absence of hair that is not always obvious, since the degree of hair loss is notably less than 50%. Homozygotes and hemizygous males weigh less than heterozygous or wild type controls. Ataxia is noticeable by 5 months and progresses as the mice age. Initially the ataxia manifests itself as a side-to-side, unsteady gait with a lateral tremor visible at rest. A delayed cerebellar cortical atrophy has been characterized in these mutants, with an apoptotic loss of granule cells beginning at 4 months of age and a necrotic loss of Purkinje cells occurring subsequently. The granule cells re-enter the cell cycle, but the Purkinje cells do not, supporting the postulate that inappropriate cell cycle re-entry of terminally differentiated neurons can induce apoptosis. Cell loss is greater in the caudal lobules of the cerebellum and is extensive by 9 to 11 months of age. Retinal degeneration is found beginning with ganglion and amacrine cell loss in the ganglion cell layer at 3 months of age, and progresses with cell loss in the inner and outer nuclear layers and reduction of rod and cone ERG responses at 4 months of age. By 10 months, the rod and cone ERG responses are gone, and at 11 months of age there isapparent cell loss in all layers of the retina. No cerebellar or retinal abnormalities were found in heterozygous females. Catalase activity and expression and total glutathione levels are increased in the cerebella of mutant mice, but not in other brain regions, and lipid hydroperoxidases are increased in brain and heart tissue. Primary granule cell cultures, but not cortical cultures, from harlequin mice show increased sensitivity to peroxide. Hemizygous males, homozygous females and hemizygous females are all viable and fertile. (Barber 1971; Falconer and Isaacson 1972; Bronson et al., 1990; Klein et al., 2002.)
