Complex Genetics of Glaucoma: Defects in CYP1B1, And Not MYOC, Cause Pathogenesis in an Early-onset POAG Patient with Double variants at both loci

Glaucoma is the second largest cause of blindness worldwide, affecting almost 60 million people (Quigley and Broman 2006). Defects in MYOC and CYP1B1 have been implicated in primary open angle glaucoma (POAG) and primary congenital glaucoma (PCG), respectively. Variants in both the genes have been detected in both the diseases indicating a higher complexity in the pathogenesis of the disease. In this context, we present here the case of a POAG patient who is found to be a compound heterozygote for CYP1B1 mutations and a homozygote for MYOC variant. None of the three nonsynonymous changes were found in 170-unrelated controls with matched age and ethnicity. Analysis of the family members reveal that proband’s younger sister, not affected, was homozygous for the MYOC variant but lacked one variant in CYP1B1. This is in contrast to other reports that showed implication of CYP1B1 in POAG. This case is unique, since both parents of the proband do not show any symptom of POAG, despite of having one defective allele for both MYOC and CYP1B1

A novel, non-stop mutation in FOXE3 causes an autosomal dominant form of variable anterior segment dysgenesis including Peters anomaly

Anterior segment dysgenesis (ASD) is a spectrum of disorders that affect the anterior ocular chamber. Clinical studies on a Newfoundland family over the past 30 years show that 11 relatives have a variable ocular phenotype ranging from microcornea to Peters anomaly, segregating as an autosomal dominant trait. To determine the molecular etiology of the variable ASD in this family, we sequenced nine functional candidate genes and identified 44 variants. A point mutation in FOXE3, which codes for a transcription factor involved in the formation of the lens and surrounding structures, co-segregated with the variable ocular phenotype. This novel mutation (c.959G>T) substitutes the stop codon for a leucine residue, predicting the addition of 72 amino acids to the C-terminus of FOXE3. Two recent reports have also identified non-stop mutations in FOXE3 in patients with variable ocular phenotypes and predict an extended protein. Although FOXE3 is a lens-specific gene, we successfully isolated complementary DNA from lymphoblasts of an affected family member, and our sequencing results show that the c.959T allele is absent, suggesting that it may be degraded at the RNA level. Though preliminary, our results challenge the notion that an extended FOXE3 protein causes ASD, and instead suggests a mechanism of haploinsufficiency in the case of non-stop mutations. This study adds to several reports that suggest that autosomal-dominant mutations within FOXE3 cause ASD and has important clinical utility, especially for the diagnosis of mildly affected patients