Glaucomas are a major cause of blindness1. Visual loss typically involves retinal ganglion cell death and optic nerve atrophy subsequent to a pathologic elevation of intraocular pressure (IOP). Some human glaucomas are associated with anterior segment abnormalities such as pigment dispersion syndrome (PDS) and iris atrophy with associated synechiae2. The primary causes of these abnormalities are unknown, and their aetiology is poorly understood. We recently characterized a mouse strain (DBA/2J) that develops glaucoma subsequent to anterior segment changes including pigment dispersion and iris atrophy3. Using crosses between mouse strains DBA/2J (D2) and C57BL/6J (B6), we now show there are two chromosomal regions that contribute to the anterior segment changes and glaucoma. Progeny homozygous for the D2 allele of one locus on chromosome 6 (called ipd) develop an iris pigment dispersion phenotype similar to human PDS. ipd resides on a region of mouse chromosome 6 with conserved synteny to a region of human chromosome 7q that is associated with human PDS (ref. 4 ). Progeny homozygous for the D2 allele of a different locus on chromosome 4 (called isa) develop an iris stromal atrophy phenotype (ISA). The Tyrp1 gene is a candidate for isa and likely causes ISA via a mechanism involving pigment production. Progeny homozygous for the D2 alleles of both ipd and isa develop an earlier onset and more severe disease involving pigment dispersion and iris stromal atrophy.
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We thank F. Farley, J. Smith, W. Whitebone, J. Worcester and K. Burns for assistance preparing the manuscript; J. Martin, C. Fickett and C. Callaghan for animal care; D. Harrison for BALB/cByJ mice; B. Taylor for BXD mice and advice; J. Wiggs for helpful discussion; J. Naggert, J. Schimenti and B. Knowles for critical reading of the manuscript; and R. Edwards for assistance configuring the slit-lamp system. This work was supported in part by National Eye Institute grant EY07758, The Foundation Fighting Blindness and grant CA34196 from the National Cancer Institute. SWMJ is an Assistant Investigator of The Howard Hughes Medical Institute.
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