Research, led by Northwestern University Feinberg School of Medicine, Chicago, Illinois and the University of Wisconsin–Madison, has reported the identification of rare gene variants in 10 of 189 unrelated primary congenital glaucoma (PCG) families. The research team published their findings in the Journal of Clinical Investigation and have additionally shown that the rare variants lead to haplo-insufficiency due to protein loss of function. The results of the study suggest that the identified variants in patients with PCG may be transmitted in an autosomal dominant pattern and with variable expressivity.
Glaucoma is estimated to affect over 60 million people worldwide with PCG, representing a severe early onset form of the disease. On a global basis, it is estimated that up to 18% of children registered in institutes for the blind have the disease. The underlying genetics of PCG is not fully understood and only a few genes have been identified of which CYP1B1, encoding a cytochrome P450 enzyme, is the most common cause of the recessive form of PCG worldwide. Elevated intraocular pressure (IOP) is a well-documented risk factor for glaucoma. Increased IOP is understood to result from defects in the aqueous humor outflow (AHO) pathway, rather than from increases in the volume of aqueous humour production. Drainage of aqueous humour is mainly through Schlemm’s canal, the endothelial of which expresses a receptor known as TEK – tunica interna endothelial cell kinase, or “Tie2”. Animal studies had previously shown that loss of TEK leads to elevated IOP, retinal ganglion cell loss and glaucoma however, before the present study no researchers had examined the role of TEK in the human form of glaucoma. The present research looked at mutations in TEK among 189 families with PCG but without mutations in the known glaucoma disease-causing genes.
Whole exome sequencing and detailed genetic analyses of samples from the recruited families uncovered 10 heterozygous novel and rare protein-altering mutations in the TEK gene, potentially identifying a molecular cause for PCG in these families. The researchers went on to conduct further research indicating that the TEK gene dosage appears to be critical for the proper development of AHO pathways and that an estimated reduction of 50% in TEK signaling seemed sufficient to lead to symptomatic development and progress of the disorder. Variable severity of the disease and variation in the age of onset may partly explain the high frequency of carriers that do not demonstrate the typical early onset phenotype seen among PCG families. In concluding their study, the researchers proposed that “an autosomal dominant model with variable expressivity, consistent with other ocular disorders of developmental origin, such as those caused by mutations in FOXC1, MYOC, PAX6, and OPA1” may best account for the data collected. The researchers additionally claim that their experimental results indicate the uncovering of “a new mechanism of PCG disease in humans” which may ultimately aid in assisting diagnoses in many new patients.