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Susana Alexandre, Julio Escribano Martínez, Raquel Atienzar Aroca, José Daniel Aroca Aguilar, Juan Manuel Bonet Fernández, Cristina Medina Trillo, Jesús Ferre Fernández, Carmen Dora Méndez Hermnández, Julián García Feijoo, Laura Morales; Role of rare FOXC2 and PITX2 variants in congenital glaucoma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1604.
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© ARVO (1962-2015); The Authors (2016-present)
Congenital glaucoma (CG) is an important cause of visual loss in children. The pathogenesis of the disease remains unexplained in most patients. Our main aim was to evaluate the role of FOXC2 and PITX2 variants in CG.
FOXC2 and PITX2 variants were analyzed by Sanger Sequencing in a cohort of 133 CG families with unknown genetic cause of CG. Possible oligogenic inheritance involving FOXC2, PITX2 and CYP1B1 was analyzed in a group of 25 CG cases who were known to carry CYP1B1 glaucoma-associated genotypes. The function of identified variants was assessed by transactivation luciferase reporter assays, protein stability and subcellular localization analyses.
Six percent of probands carried four rare FOXC2 variants in heterozygosis. In addition, 8% of CG cases with CYP1B1 glaucoma-associated genotypes carried heterozygous and rare PITX2 variants. Furthermore, two of the identified variants (FOXC2: c.1183C>A, p.(H395N); and PITX2: c.535C>A, p.(P179T)) are novel. Three identified amino acid substitutions (FOXC2: p.(C498R) and p.(H395N); PITX2: p.(P179T)) showed partial transactivation alteration.
The increased frequency of rare FOXC2 and PITX2 variants with mild functional alterations in PCG patients, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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