April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Hypo- and hypermorphic FOXC1 mutations in dominant primary congenital glaucoma.
Author Affiliations & Notes
  • Cristina Medina Trillo
    Human Genetics Laboratory, Medical School. University of Castilla-La Mancha, Albacete, Spain
    Cooperative Research Network on Age-Realted Ocular Pathology, Visual and Life Quality. RETICS., Carlos III Health Institute, Madrid, Spain
  • Jesús Jose Ferre Fernández
    Human Genetics Laboratory, Medical School. University of Castilla-La Mancha, Albacete, Spain
    Cooperative Research Network on Age-Realted Ocular Pathology, Visual and Life Quality. RETICS., Carlos III Health Institute, Madrid, Spain
  • Jose Daniel Aroca-Aguilar
    Human Genetics Laboratory, Medical School. University of Castilla-La Mancha, Albacete, Spain
    Cooperative Research Network on Age-Realted Ocular Pathology, Visual and Life Quality. RETICS., Carlos III Health Institute, Madrid, Spain
  • Laura Morales-Fernancez
    Cooperative Research Network on Age-Realted Ocular Pathology, Visual and Life Quality. RETICS., Carlos III Health Institute, Madrid, Spain
    Ophthalmology Service. San Carlos Hospital Research Institute, . Complutense University of Madrid, Madrid, Spain
  • Carmen Mendez-Hernandez
    Cooperative Research Network on Age-Realted Ocular Pathology, Visual and Life Quality. RETICS., Carlos III Health Institute, Madrid, Spain
    Ophthalmology Service. San Carlos Hospital Research Institute, . Complutense University of Madrid, Madrid, Spain
  • Carmen Ayuso
    Ophthalmology Service, Jiménez Díaz Foundation, CIBERER, Madrid, Spain
  • Julian García
    Cooperative Research Network on Age-Realted Ocular Pathology, Visual and Life Quality. RETICS., Carlos III Health Institute, Madrid, Spain
    Ophthalmology Service. San Carlos Hospital Research Institute, . Complutense University of Madrid, Madrid, Spain
  • Julio Escribano
    Human Genetics Laboratory, Medical School. University of Castilla-La Mancha, Albacete, Spain
    Cooperative Research Network on Age-Realted Ocular Pathology, Visual and Life Quality. RETICS., Carlos III Health Institute, Madrid, Spain
  • Footnotes
    Commercial Relationships Cristina Medina Trillo, None; Jesús Ferre Fernández, None; Jose Daniel Aroca-Aguilar, None; Laura Morales-Fernancez, None; Carmen Mendez-Hernandez, None; Carmen Ayuso, None; Julian García, None; Julio Escribano, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 3805. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: 539 genetics • 735 trabecular meshwork  
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