VAV2 and VAV3 as candidate disease genes for spontaneous glaucoma in mice and humans.
BACKGROUND
Glaucoma is a leading cause of blindness worldwide. Nonetheless, the mechanism of its pathogenesis has not been well-elucidated, particularly at the molecular level, because of insufficient availability of experimental genetic animal models.


RESULTS
Here we demonstrate that deficiency of Vav2 and Vav3, guanine nucleotides exchange factors for Rho guanosine triphosphatases, leads to an ocular phenotype similar to human glaucoma. Vav2/Vav3-deficient mice, and to a lesser degree Vav2-deficient mice, show early onset of iridocorneal angle changes and elevated intraocular pressure, with subsequent selective loss of retinal ganglion cells and optic nerve head cupping, which are the hallmarks of glaucoma. The expression of Vav2 and Vav3 tissues was demonstrated in the iridocorneal angle and retina in both mouse and human eyes. In addition, a genome-wide association study screening glaucoma susceptibility loci using single nucleotide polymorphisms analysis identified VAV2 and VAV3 as candidates for associated genes in Japanese open-angle glaucoma patients.


CONCLUSIONS
Vav2/Vav3-deficient mice should serve not only as a useful murine model of spontaneous glaucoma, but may also provide a valuable tool in understanding of the pathogenesis of glaucoma in humans, particularly the determinants of altered aqueous outflow and subsequent elevated intraocular pressure.
Fujikawa
Keiko
K
Department of Pathology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. fujikawa@med.hokudai.ac.jp
Iwata
Takeshi
T
Inoue
Kaoru
K
Akahori
Masakazu
M
Kadotani
Hanako
H
Fukaya
Masahiro
M
Watanabe
Masahiko
M
Chang
Qing
Q
Barnett
Edward M
EM
Swat
Wojciech
W
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics; D005123:Eye / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D005901:Glaucoma / Q000235:genetics*; D005902:Glaucoma, Open-Angle / Q000208:ethnology / Q000235:genetics; D006801:Humans; D006871:Hydrophthalmos / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007429:Intraocular Pressure / Q000187:drug effects; D007564:Japan; D000077338:Latanoprost; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration; D009898:Optic Disk / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011461:Prostaglandins F, Synthetic / Q000627:therapeutic use; D051567:Proto-Oncogene Proteins c-vav / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000959:Antihypertensive Agents; D011461:Prostaglandins F, Synthetic; D051567:Proto-Oncogene Proteins c-vav; C093651:VAV2 protein, human; C496621:VAV3 protein, human; C490565:Vav2 protein, mouse; C496622:Vav3 protein, mouse; D000077338:Latanoprost