Exploring correlation between gene expression, cataract morphology

Researchers explored messenger RNA in pediatric cataracts linked to multiple genes that have been previously identified as being associated with pediatric cataracts. 

Pediatric cataracts are the cause of up to 15.3% of childhood blindness cases, and while different types of pediatric cataracts have distinct etiologies and morphologies, almost nothing is known about the genetic pathways that underlie these cataracts.

While pediatric cataracts can be treated, surgery is almost always an emergency.

“We have studies of gene mutations in human families,” said Joyti Matalia, MBBS, Pediatric Ophthalmology Services and Grow Lab in Bangalore, India.

The mutations have been studied extensively in animal models, according to Dr. Matalia.

“In humans, these studies have been done only in blood and never in lens matte,” she said. “The causes of pediatric cataract have been investigated. There is no report on the molecular mechanisms of congenital cataracts or on gene expression in these cataracts.”

Dr. Matalia described an investigation of gene expression and molecular pathways that lead to different types of pediatric cataracts. Researchers explored messenger RNA in pediatric cataracts linked to multiple genes associated with pediatric cataracts.

Five categories
The study classified pediatric cataracts into five different categories.

Congenital cataracts were classified as either infectious, associated with rubella, cytomegalovirus, or a combination of the two infections, or noninfectious, whether linked with an inherited condition or lens opacification due to posterior capsular anomalies.

Acquired cataracts were classified as postnatal, cataracts which developed anytime during childhood after the first birthday, secondary cataracts that developed following other ocular diseases such as uveitis, or traumatic cataracts.

Three types of genes are known to be associated with pediatric cataracts. Structural genes maintain transparency of the lens.

Transcription factor genes play roles in lens development. Fibrotic genes maintain the physical integrity of the lens.
Errors in the expression of any of these genes has the potential to result in early cataracts.

Lens structural genes
The group explored three lens structural genes, including:
> AQP-0 is responsible for aquaporin-0, a protein which maintains lens transparency. Defects in this protein can result in inherited cataracts and congenital glaucoma.
> HSPA-4 is responsible for heaths shock protein A-4, found in lens epithelium and fibers. Mutations are reported to result in inherited cataracts.
> CRYG-C is responsible for crystallin gamma-C, a protein which maintains lens transparency. Mutations are associated with autosomal dominant nuclear cataracts.

Four lens transcription factor genes were also included. They are:
> MAF codes for musculoaponeurotic fibrosarcoma oncogene, which is involved in the regulation of crystallins. Defects cause cataracts and anterior segment dysgenesis.
> TDRD-7 codes for Tudor domain containing protein 7, which regulates genes critical for lens development. Defects can give rise to cataracts, microcornea and coloboma.
> FOXE-3 codes for forkhead box 3, which may play a critical role in lens development. Defects have been associated with cataracts as well as anterior segment dysgenesis.
> PITX-3 codes for pituitary homeobox 3, also suspected of playing a critical role in lens development. Defects have been associated with cataracts and anterior segment abnormalities.

Four genes have been associated with profibrotic factors. These factors are typically seen in a fibrotic cascade in skin and other tissues, Dr. Matalia said, and might be active in cataract formation. These genes include:
> TGF-β codes for transforming growth factor beta.
> α-SMA codes for alpha smooth muscle actin.
> VIM codes for vimentin
> BMP-7 codes for bone morphogenic protein-7.

Researchers conducted a prospective cross-sectional study using lens material extracted during routine cataract surgery on 90 patients younger than 16 years of age. There were eight study groups, postnatal cataract (nine patients), secondary cataracts (13 patients), traumatic cataracts (13 patients), rubella cataracts (nine patients), rubella + CMV (eight patients), CMV cataracts (nine patients), prenatal cataracts (nine patients), and posterior capsular anomalies (10 patients).

A control group of 10 patients had clear subluxated lenses.

Among the structural genes, only AQP-0 and CRYG-C are highly expressed in infectious CMV and prenatal cataracts, Dr. Matalia noted, concluding that prenatal cataracts likely derive from transcriptional hyperactivity of AQP-0 and CRYG-C. HSPA-4 appears to play no role in the development of prenatal cataracts.

Among the transcription factor genes, TDRD-7 is expressed in the CMV group, supporting the involvement of both AQP-0 and CRYG-C. This same pathway is inhibited in rubella cataracts.

FOXE-3 also shows higher expression in the prenatal group, but PITX-3 and MAF expression is similar to the control group.
Fibrotic gene expression shows a significant decrease in both the rubella and rubella + CMV groups, suggesting that the fibrotic pathways seen in other tissues do not contribute to the formation of cataracts in younger patients.

“This is the first preliminary study to talk about gene expression in lens matter from pediatric human cataracts,” Dr. Matalia said. “There is definitely a correlation between gene expression and cataract morphology. If we are able to find the precise pathway and a drug to block it, we can modify gene expression using target-specific therapy.” 

Disclosures:

Joyti Matalia, MBBSE: jyoti.matalia@gmail.com
This article was adapted from Matalia’s presentation at the 2018 meeting of the American Academy of Ophthalmology. Matalia has no financial interests to disclose.