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Cristina Medina Trillo, Jesús Jose Ferre Fernández, Jose Daniel Aroca-Aguilar, Laura Morales-Fernancez, Carmen Mendez-Hernandez, Carmen Ayuso, Julian García, Julio Escribano; Hypo- and hypermorphic FOXC1 mutations in dominant primary congenital glaucoma.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3805.
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Primary congenital glaucoma is the commonest childhood glaucoma and it is produced by developmental abnormalities of the anterior segment of the eye. Autosomal-recessive inheritance is well documented in this disease, mainly due to CYP1B1 mutations, but dominant cases have also been reported. FOXC1 gene encodes a member of the FOX class of transcription factors, which are involved in the regulation of ocular development. Mutations in this gene cause a spectrum of autosomal dominant and ocular anterior eye segment defects, including Axenfeld-Rieger syndrome, with increased glaucoma risk and varying degrees of iris or extra-ocular abnormalities. Our main purpose in this work has been to evaluate the role of FOXC1 sequence variations in dominant primary congenital glaucoma.
Eleven probands diagnosed with primary congenital glaucoma, generally before 3 years, were recruited at the Ophthalmology Department of “Hospital Clínico San Carlos” (Madrid, Spain). The presence of FOXC1 variants was determined by automatic Sanger Sequencing. The identified FOXC1 variants were cloned into the expression vector pcDNA3.1 (-). Transcriptional activity of the identified variants, transiently expressed in the HEK-293T human cell line, was assessed by luciferase assays.
Three dominant probands carried three different coding heterozygous FOXC1 mutations. All these mutations were associated with bilateral glaucoma and variable disease onset ranging from 1 to 30 years in the index cases. The functional study showed that two of the identified mutations increased the transcriptional activity, (ranging approximately from 160% to almost 200%) and were classified as hypermorphic variants. In contrast, the activity of the remaining variant was only 20% compared to the wild-type protein, showing that it is a hypomorphic allele.
Rare coding FOXC1variations of are present in 27.3% of the studied families, diagnosed with dominant PCG. These results provide strong evidence for the role of FOXC1 hypo- and hypermorphic variants in primary congenital glaucoma with variable age onset.
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