The overall prevalence of glaucoma was 58.5% and was similar for both genes (53.3% for FOXC1 vs 60.9% for PITX2, P=0.59), however, the median age at glaucoma diagnosis was significantly lower in FOXC1 (6.0±13.0 years) compared with PITX2 carriers (18.0±10.6 years, P=0.04).
Investigations of other glaucoma-related genes, such as PITX2, FOXC1, and CYP1B1, are enabling a better understanding of anterior segment development and its relation to glaucoma.
The human Mf1 homolog FREAC3 is a candidate gene for ocular dysgenesis and glaucoma mapping to chromosome 6p25-pter, and deletions of this region are associated with multiple developmental disorders, including hydrocephaly and eye defects.
FOXC1 mutations result in Axenfeld-Rieger syndrome, a disorder characterized by a broad spectrum of malformations of the anterior segment of the eye and an elevated risk for glaucoma.
In the present study, current medical therapies do not successfully lower intraocular pressure or prevent progression of glaucoma in patients with ARM who have FOXC1 or PITX2 alterations.
In this family harboring both structural alterations, two patients who carried the GJA1 (Ala253Val) and FOXC1 (Trp152STOP) mutations developed less severe glaucoma compared with family members presenting the FOXC1 (Trp152STOP) mutation alone.
Haploinsufficiency through mutation or deletion of the forkhead transcription factor, FOXC1, causes Axenfeld-Rieger anomaly, which manifests as a range of anterior segment eye defects and glaucoma.
Our findings demonstrate that, although mutations of FKHL7 result in anterior-segment defects and glaucoma in some patients, it is probable that at least one more locus involved in the regulation of eye development is also located at 6p25.
These results support that moderate and variable FOXC1 transactivation changes are associated with moderate goniodysgenesis, dominant glaucoma and remarkable phenotypic variability.
Mutations in the forkhead transcription-factor gene (FOXC1), have been shown to cause defects of the anterior chamber of the eye that are associated with developmental forms of glaucoma.
Mutations in the human FOXC1 transcription factor gene underlie Axenfeld-Rieger (AR) syndrome, a disorder characterized by anterior segment malformations in the eye and glaucoma.
FOXC1 mutations underlie Axenfeld-Rieger syndrome, an autosomal dominant disorder that is characterized by a spectrum of ocular and nonocular phenotypes and results in an increased susceptibility to glaucoma.
Human FOXC1 heterozygous mutations are known to affect eye development, causing a spectrum of glaucoma-associated anomalies (Axenfeld-Rieger syndrome, ARS; MIM no.601631).
Ten patients (7.5%) with no family history of glaucoma carried five different rare heterozygous FOXC1 variants with both increased (rs77888940:C>G, c.-429C>G, rs730882054:c.1134_144del(CGGCGGCGCGG), p.(G380Rfs*144) and rs35717904:A>T, c.*734A>T) and decreased (rs185790394: C>T, c.-244C>T and rs79691946:C>T, p.(P297S)) transactivation, ranging from 50 to 180% of the wild-type activity.
The molecular diagnosis for glaucoma included two cases with compound heterozygous or homozygous pathogenic alleles in CYP1B1 and one family with a dominant pathogenic variant in FOXC1; the second genetic diagnosis for the additional systemic features included compound heterozygous mutations in NPHS1 in one family and a heterozygous 18q23 deletion in another pedigree.