A Phenotypic Screen for New Mouse Models of Pigmentary Glaucoma Among Coat Color Variants

Abstract

Abstract: : Purpose: The genetic basis of pigment dispersion syndrome and pigmentary glaucoma in humans remains unknown. In mice, mutations in two genes encoding melanosomal proteins, Gpnmb and Tyrp1, initiate a pigment dispersing iris disease that ultimately causes glaucoma. The goal of this experiment was to screen mouse strains with mutations in other genes influencing melanosomes in hopes of uncovering new clues to the molecules and mechanisms underlying the pigment dispersion phenotype. Methods: As one of the largest repositories of variant mouse strains in the world, the collection of mice housed at The Jackson Laboratory represents a significant genetic resource. Among these are several strains harboring mutations influencing melanosomes that contribute to coat color. Aging cohorts of 15 coat color variant strains were screened by slit–lamp examination for indices of pigment dispersion and slit–like transillumination defects. Mutations were previously known for 14 of the strains. The mutation within one strain (nm2798) was previously unknown and therefore characterized here using genetic and molecular techniques. Results: A total of four new strains with previously unrecognized pigment dispersion phenotypes were identified. Three were within strains with known mutations (LT/SvEi, Tyrp1; B6.Lyst^bg–J, Lyst; and B6.mitf^mi–vit, mitf). The fourth strain exhibiting pigment dispersion was nm2798, which we show contains a mutation within Dct (also referred to as Tyrp2). Although several strains exhibited various degrees of hypopigmented irides, no strains exhibited a slit–like pattern of transillumination. Interestingly, the degree of iris hypopigmentation often failed to correlate to coat color, suggesting that the biology of iris pigmentation differs in at least some basic regards from the biology of hair pigmentation. Conclusions: The identification of pigment dispersion phenotypes in four additional strains of mice with altered melanosomes significantly strengthens the hypothesis that aberrant melanosomal processes contribute to a susceptibility of the iris toward pigment dispersion. Our future studies in mice will aim to further dissect the nature of the melanosomal insults and the pathological progression they initiate. Based on these findings, genes encoding melanosomal proteins remain excellent candidates of human pigment dispersion syndrome and pigmentary glaucoma.

Keywords: genetics • iris • melanocytes