Abstract
Congenital glaucoma (CG) is a severe and inherited childhood optical neuropathy that leads to irreversible visual loss and blindness in children. CG pathogenesis remains largely unexplained in most patients. Herein we have extended our previous studies to evaluate the role of FOXC2 and PITX2 variants in CG. Variants of the proximal promoter and transcribed sequence of these two genes were analyzed by Sanger sequencing in a cohort of 133 CG families. To investigate possible oligogenic inheritance involving FOXC2 or PITX2 and CYP1B1, we also analyzed FOXC2 and PITX2 variants in a group of 25 CG cases who were known to carry CYP1B1 glaucoma-associated genotypes. The functional effect of three identified variants was assessed by transactivation luciferase reporter assays, protein stability and subcellular localization analyses. We found eight probands (6.0%) who carried four rare FOXC2 variants in the heterozygous state. In addition, we found an elevated frequency (8%) of heterozygous and rare PITX2 variants in the group of CG cases who were known to carry CYP1B1 glaucoma-associated genotypes, and one of these PITX2 variants arose de novo. To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, p.(H395N); and PITX2: c.535C>A, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: p.(C498R) and p.(H395N); PITX2: p.(P179T)). In summary, the increased frequency in PCG patients of rare FOXC2 and PITX2 variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.
Highlights
Primary congenital glaucoma (PCG; MIM# 231300) is a severe and irreversible neonatal or infantile optic neuropathy of uncertain pathogenesis
Whole-exome sequencing revealed that mutations in the angiopoietin receptor TEK (TEK, MIM# 600221) underlie PCG with variable expressivity [9] and that rare and hypermorphic G-PATCH DOMAIN-CONTAINING PROTEIN 3 (GPATCH3, MIM# 617486) variants are present in a some congenital glaucoma (CG) cases [10]
To further investigate the role in CG of variants of genes involved in ocular development we have extended our previous genetic studies on a large cohort of 133 apparently unrelated PCG families, in which we reported an increased frequency of rare and functionally altered FOXC1 variants [18, 20]
Summary
Primary congenital glaucoma (PCG; MIM# 231300) is a severe and irreversible neonatal or infantile optic neuropathy of uncertain pathogenesis. The immature iridocorneal angle appearance observed clinically indicates that it results from arrested maturation of tissues derived from cranial neural crest cells This alteration leads to increased aqueous humor (AH) outflow resistance, elevated intraocular pressure (IOP) and optic nerve degeneration. Classical linkage analysis has identified loss-of-function variants in CYP1B1 [7] and LATENT TRANSFORMING GROWTH FACTOR-β-BINDING PROTEIN 2 (LTBP2, MIM# 602091) [8] as the cause of the disease in some patients. The genetic heterogeneity present in PCG, along with the frequent incomplete penetrance and variable expressivity, even in patients with null CYP1B1 genotypes [13], strongly indicates the participation of modifier genetic and/or environmental factors in the pathogenicity of this type of glaucoma. Previous studies from our laboratory have provided evidence for the role of rare FOXC1 variants with moderate functional dysregulation as either causative of modifier factors in CG [18,19,20]
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