Cataract gene regulates protein expression in lens

A mutation involved in childhood cataracts has proved to be the first known instance of a genetic developmental disorder of organs mediated through disruption of post-transcriptional regulation, a new study in Science from an international collaboration including Saudi researchers shows.

Congenital cataracts, a clouding of lens fibre cells that often leads to blindness, commonly result from mutations in genes that encode structural proteins within the lens. They occur in one in every 30,000 births in the United States, but are more common in consanguineous cultures such as Saudi Arabia, where the incidence reaches 1 in 2,500 births.

An international group of geneticists and clinicians took a closer look at the chromosomes of a child with cataract. They identified a mutation in a gene that encodes TDRD7, a member of a family of proteins that form RNA granules (RGs). RGs regulate gene expression by controlling the fate of mRNAs, but until now were not known to influence organogenesis.

Independent confirmation came from studies of four siblings from a consanguineous marriage in Kuwait that had juvenile cataracts, two of whom had also had glaucoma: a neuropathology of the eye caused by increased intraocular pressure and stress to the optic nerve. The researchers used homozygosity mapping – to quickly find the same mutated genes inherited from both parents – to show that each sibling had mutations in TDRD7.

"The role of TDRD7 in glaucoma and cataracts is now known to be very important, and could provide insight into the underlying pathophysiology," says Richard Maas, a geneticist at Brigham and Women's Hospital and Harvard Medical School, who led the study.

In knockout mouse models of Tdrd7, the mice also developed glaucoma and cataracts, confirming that mutations in TDRD7 result in cataract and improper development of the eye. The next step was to see how a gene encoding an mRNA regulatory protein such as a TDRD7, could impact the development of an organ system.

Microarray analysis revealed that the expression levels of a specific set of mRNAs are influenced by the expression of TDRD7 including those encoding crystallins, which are structural proteins that give the eye it's high refractive index and optical clarity. It also influences the expression of PAX6, a gene involved in fibre cell differentiation, amongst many other cellular interactions.

Of surprise to the team was that TDRD7 interacts with other types of RNA granules, including processing bodies and stress granules that work to protect cells from stressful stimuli, suggesting that TDRD7 may also serve a protective function.

Next, the team plans to see how common mutations in TDRD7 are in patients with cataract and glaucoma. They are currently trying to figure out how the TDRD7-containing RNA-granules interact with mRNA and other RGs. In doing so, investigators may shed new light on two debilitating eye diseases, and uncover a new way the cell regulates gene expression in cells.

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