The albino mutation of tyrosinase alters ocular angiogenic responsiveness
We have observed substantial differences in angiogenic responsiveness in mice and have mapped the genetic loci responsible for these differences. We have found that the albino mutation is one of the loci responsible for such differences. Using B6.A consomic strains, we determined that chromosome 7 bears a locus that inhibits VEGF-induced corneal neovascularization. F2 crosses between B6.A<Chromosome 7> consomic mice and C57BL/6J parents along with AXB and BXA recombinant inbred strains demonstrated highest linkage near the tyrosinase gene. This region was named AngVq4. Congenic animals confirmed this locus, but could not demonstrate that the classical tyrosinase albino (c) mutation was causative because of the existence of additional linked loci in the congenic region. However, in 1970, a second tyrosinase albino mutation (c-2J) arose in the C57BL/6J background at Jackson Labs. Testing this strain (C57BL/6J<c-2J>) demonstrated that the albino mutation is sufficient to completely explain the alteration in angiogenic response that we observed in congenic animals. Thus, we conclude that the classical tyrosinase mutation is responsible for AngVq4. In contrast to the cornea, where pigmented animals exhibit increased angiogenic responsiveness, iris neovascularization was inhibited in pigmented animals. These results may partially explain increased aggressiveness in amelanotic melanoma, as well as ethnic differences in diabetic retinopathy and macular degeneration.
KeywordsQTL mapping Pigment Albino Consomic mouse Cornea Iris DOPA DHI 5,6-Dihydroxyindole
- 2.Rogers MS, Rohan RM, Birsner AE, D’Amato RJ (2003) Genetic loci that control vascular endothelial growth factor-induced angiogenesis. Faseb J 17(14):2112–2114Google Scholar
- 4.Nakai K, Rogers MS, Baba T, Funakoshi T, Birsner AE, Luyindula DS, D’Amato RJ (2009) Genetic loci that control the size of laser-induced choroidal neovascularization. Faseb J 23(7):2235–2243Google Scholar
- 7.Shaked Y, Bertolini F, Man S, Rogers MS, Cervi D, Foutz T, Rawn K, Voskas D, Dumont DJ, Ben-David Y, Lawler J, Henkin J, Huber J, Hicklin DJ, D’Amato RJ, Kerbel RS (2005) Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 7(1):101–111PubMedGoogle Scholar
- 16.Wang S, Basten CJ, Zeng Z-B (2007) Windows QTL Cartographer 2.5. 2.5 ednGoogle Scholar
- 21.Pham CL, Leong SL, Ali FE, Kenche VB, Hill AF, Gras SL, Barnham KJ, Cappai R (2009) Dopamine and the dopamine oxidation product 5,6-dihydroxylindole promote distinct on-pathway and off-pathway aggregation of alpha-synuclein in a pH-dependent manner. J Mol Biol 387(3):771–785PubMedCrossRefGoogle Scholar