Hypo- and hypermorphic FOXC1 mutations in dominant glaucoma: transactivation and phenotypic variability

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Dominant glaucoma is an irreversible optic neuropathy often linked to high intraocular pressure and early onset.
• The forkhead box C1 (FOXC1) gene's role in dominant glaucoma requires further investigation.

Purpose of the Study:

• To investigate the role of FOXC1 gene mutations in Spanish patients with dominant glaucoma.
• To functionally characterize identified FOXC1 variants and their impact on glaucoma pathogenesis.

Main Methods:

• Nucleotide variation screening of the FOXC1 gene's promoter and exon in twelve Spanish probands.
• Functional analyses including transcriptional activity, protein stability, DNA binding, and subcellular localization assays.

Main Results:

• Four distinct FOXC1 mutations were identified in 33.3% of probands, exhibiting significant phenotypic variability.
• Three novel variants (p.Y47X, p.I126S, p.G447_G448insDG) were found, with the first report of hypermorphic FOXC1 mutations.
• Mutations were classified as hypermorphic (gain-of-function) or hypomorphic (loss-of-function), affecting protein stability, DNA binding, and interactions.

Conclusions:

• FOXC1 gene mutations are associated with dominant glaucoma and considerable phenotypic variability.
• Both hypermorphic and hypomorphic FOXC1 alleles contribute to glaucoma pathogenesis through altered molecular mechanisms.
• FOXC1 transactivation changes correlate with goniodysgenesis and dominant glaucoma, highlighting its critical role.