Genetic context determines susceptibility to intraocular pressure elevation in a mouse pigmentary glaucoma

BACKGROUND: DBA/2J (D2) mice develop an age-related form of glaucoma. Their eyes progressively develop iris pigment dispersion and iris atrophy followed by increased intraocular pressure (IOP) and glaucomatous optic nerve damage. Mutant alleles of the Gpnmb and Tyrp1 genes are necessary for the iris disease, but it is unknown whether alleles of other D2 gene(s) are necessary for the distinct later stages of disease. We initiated a study of congenic strains to further define the genetic requirements and disease mechanisms of the D2 glaucoma. RESULTS: To further understand D2 glaucoma, we created congenic strains of mice on the C57BL/6J (B6) genetic background. B6 double-congenic mice carrying D2-derived Gpnmb and Tyrp1 mutations develop a D2-like iris disease. B6 single-congenics with only the Gpnmb and Tyrp1 mutations develop milder forms of iris disease. Genetic epistasis experiments introducing a B6 tyrosinase mutation into the congenic strains demonstrated that both the single and double-congenic iris diseases are rescued by interruption of melanin synthesis. Importantly, our experiments analyzing mice at ages up to 27 months indicate that the B6 double-congenic mice are much less prone to IOP elevation and glaucoma than are D2 mice. CONCLUSION: As demonstrated here, the Gpnmb and Tyrp1 iris phenotypes are both individually dependent on tyrosinase function. These results support involvement of abnormal melanosomal events in the diseases caused by each gene. In the context of the inbred D2 mouse strain, the glaucoma phenotype is clearly influenced by more genes than just Gpnmb and Tyrp1. Despite the outward similarity of pigment-dispersing iris disease between D2 and the B6 double-congenic mice, the congenic mice are much less susceptible to developing high IOP and glaucoma. These new congenic strains provide a valuable new resource for further studying the genetic and mechanistic complexity of this form of glaucoma

Absence of glaucoma in DBA/2J mice homozygous for wild-type versions of Gpnmb and Tyrp1

BACKGROUND: The glaucomas are a common but incompletely understood group of diseases. DBA/2J mice develop a pigment liberating iris disease that ultimately causes elevated intraocular pressure (IOP) and glaucoma. We have shown previously that mutations in two genes, Gpnmb and Tyrp1, initiate the iris disease. However, mechanisms involved in the subsequent IOP elevation and optic nerve degeneration remain unclear. RESULTS: Here we present new mouse strains with Gpnmb and/or Tyrp1 genes of normal function and with a DBA/2J genetic background. These strains do not develop elevated IOP or glaucoma with age. CONCLUSION: These strains provide much needed controls for studying pathogenic mechanisms of glaucoma using DBA/2J mice. Given the involvement of Gpnmb and/or Tyrp1 in areas such as immunology and tumor development and progression, these strains are also important in other research fields

Absence of glaucoma in DBA/2J mice homozygous for wild-type versions of <it>Gpnmb </it>and <it>Tyrp1</it>

Abstract Background The glaucomas are a common but incompletely understood group of diseases. DBA/2J mice develop a pigment liberating iris disease that ultimately causes elevated intraocular pressure (IOP) and glaucoma. We have shown previously that mutations in two genes, Gpnmb and Tyrp1, initiate the iris disease. However, mechanisms involved in the subsequent IOP elevation and optic nerve degeneration remain unclear. Results Here we present new mouse strains with Gpnmb and/or Tyrp1 genes of normal function and with a DBA/2J genetic background. These strains do not develop elevated IOP or glaucoma with age. Conclusion These strains provide much needed controls for studying pathogenic mechanisms of glaucoma using DBA/2J mice. Given the involvement of Gpnmb and/or Tyrp1 in areas such as immunology and tumor development and progression, these strains are also important in other research fields.</p

Absence of glaucoma in DBA/2J mice homozygous for wild-type versions of and -2

<p><b>Copyright information:</b></p><p>Taken from "Absence of glaucoma in DBA/2J mice homozygous for wild-type versions of and "</p><p>http://www.biomedcentral.com/1471-2156/8/45</p><p>BMC Genetics 2007;8():45-45.</p><p>Published online 3 Jul 2007</p><p>PMCID:PMC1937007.</p><p></p>on. . Side view dimensions of the anterior chamber. D2-eyes show no IPD but have a distinct form of ISA where the iris appears 'roughened'. D2-eyes have no transillumination defects and normal anterior chamber morphology (more than 20 eyes were analyzed from a variety of ages, images shown here are from a 13 months old mouse). . IOP measurements in D2-mice. Individual IOP readings are plotted as circles. The solid horizontal line indicates 21 mmHg, a value considered to be glaucoma-suspect in people. No 'high' IOP readings were seen in 97 eyes measured. Also, there is no significant change in IOP levels comparing 4 months old D2-mice to the 8, 10, 12 or 14 months old groups (p > 0.37 for all comparisons)