News at Medicine - December 2010 - Study identifies gene mutation in unusual eye disease

Study identifies gene mutation in unusual eye disease
December 17, 2010
Lance Doucette, a PhD student supervised by Dr. Terry-Lynn Young, is the first author of a paper just published online in the European Journal of Human Genetics.

The paper, titled A novel, non-stop mutation in FOXE3 causes an autosomal dominant form of variable anterior segment dysgenesis including Peters anomaly, identifies the genetics basis of a rare eye disease found in a large Newfoundland family. The discovery of the molecular etiology of this rare eye disease is the culmination of clinical studies over the past 30 years on a Newfoundland family with 11 relatives with mild to severe eye disease, ranging from microcornea to Peters anomaly. The gene discovery has immediate clinical utility as it provides presymptomatic and diagnostic testing to family members.

Geneticist Dr. Jane Green saw the first patient in this study in 1979. The infant had an opaque cornea that was mostly white where it should have been clear. Other family members had eye problems including very early cataracts, but the infant had the most severe case that had been seen.

“Over the years ophthalmologist Dr. Gordon Johnson and I followed this family and in 1986 published a clinical paper,” explained Dr. Green. “In the 1980s there was no possibility of finding the relevant gene but as molecular techniques improved it became more feasible.”

Mr. Doucette conducted a functional gene sequencing approach to the problem and identified a single base change in a transcription factor gene, FOXE3, which codes for a protein involved in the formation of the lens of the human eye. This novel mutation is unusual in that it disrupts the stop codon at the 3’ end of the gene. Although predicted to add another 72 amino acids to the C-terminus of the protein, our RNA studies suggest that the aberrant message is degraded before it leaves the nucleus. This is one of several eye conditions being molecularly investigated by Mr. Doucette as part of a team study on hereditary eyes disease in the Newfoundland population funded by the Faculty of Medicine, the Janeway Foundation and Genome Canada (AMGGI: Co-Principal Investigator Dr. Terry-Lynn Young).

The clinical impact is immediate. “Now there is a genetic test to determine if an individual carries this disease,” said Dr. Green.  “Family members who had been concerned about the risk of having an affected child are now considering having children.”

Dr. Green said that the identification of this gene is an example of a unique and rare condition that can have a big impact. “Even though it’s just one family, there were 14 siblings with all their children and grandchildren, so concern about the risk of the disease affected a lot of people.”

She noted that this discovery is an example of a partnership with members of a family that worked out, even if it took many years. “It’s nice that someone will come and say to me ‘thank you’ after 30 years.”

Peters anomaly is a rare congenital disorder characterized by corneal opacities and adhesions of the cornea to the iris or lens. Peters anomaly and other ocular malformations that affect the anterior chamber of the eye, including the cornea, iris, lens, and iridocorneal angle, belong to a spectrum of disorders collectively known as anterior segment dysgenesis (ASD).

The results of this study implicate FOXE3 in the pathology of ASD and corroborate other recent reports of ASD cases with FOXE3 mutations. Therefore, mutations within FOXE3 may explain currently unsolved ASD cases and should be screened for. Discovery of genes and mutations causing ASD in families is of particular clinical relevance. A molecular diagnosis of ASD cases through mutation screening can provide accurate risks of recurrence, especially in light of mild or subclinical phenotypes, which may show progression over time such as those seen in the family described in this study.