Iris and Retinal Pigment Epithelium Atrophy in Rab38cht/cht Mice

Abstract

Abstract: : Purpose: Mutations of genes needed for melanocyte function can result in oculocutaneous albinism. RAB38, a small GTP binding protein, demonstrates a similar expression profile to melanocytic genes. Rab38^cht/Rab38^cht mice exhibit a light brown coat color similar to mice with a mutation in tyrosinase–related protein 1 (Tyrp1), a mouse model for oculocutaneous albinism. The aim of the study is to characterize the ocular phenotype in these mice. Methods: Homozygous cht/cht , heterozygous, and wild–type mice were examined clinically, electrophysiologically, and histologically, including electron microscopy, at several ages. Results: Cht/cht, but not cht/+ mice, showed mild peripheral iris transillumination defects by 2 months of age that progressed in approximately 1/3^rd of mice to clinical iris atrophy over a year of age. Approximately 60% of cht/cht mice (20 of 30) and 12.5% of cht/+ mice (1 of 8) over a year of age develop patchy depigmented areas of RPE. Electroretinographic responses in 3 month old cht/cht mice showed a statistically larger b–wave amplitude in the scotopic range when compared to wild–type mice. Histopathological comparisons of cht/cht and wild–type eyes at 5 months of age showed no significant difference except less pigmentation. However, in mice over a year of age, degeneration of the iris melanocytes and RPE were evident in cht/cht mice; a milder degernative RPE was noted in cht/+ mice. Ultrastructural studies showed early degeneration and atrophy of the iris melanocyte and RPE in cht/cht mice at 3 months of age. Mutation screening of Rab38 in 12, lightly–pigmented albino patients, in 8 HPS and 11 HPS–like patients, and in 17 patients with pigmentary glaucoma, revealed no mutations and four novel polymorphisms . Conclusions: Cht mice show ocular findings reminiscent of albinism with degenerative changes in the iris melanocyte and RPE. They provide a useful model for studying melanosome biology in ocular tissues.

Keywords: retinal pigment epithelium • iris • genetics