IISc researchers find unknown gene creating smaller eye lenses

The combination of a freshwater fish species, two rural children and six years of gruelling investigative work has allowed researchers to find a mutated gene that causes a serious eye defect in some Indian children.

Microspherophakia (MSP) is a congenital eye defect in which the size of the eye lens is smaller than normal that inevitably leads to second-stage glaucoma in children if untreated. It has concerned researchers because not all the genetic factors that cause this defect are known.

The condition has been described in different ethnic groups since 1901, mostly in Asia and North Africa. The exact incidence rate is not known but scientific literature postulates that 1.2% out of 5.6 million Indian children presenting for lens abnormalities annually have microspherophakia.

While scientists know of three mutated genes in the human body that can cause this eye defect, information gaps mean that thousands of children worldwide are going undetected until glaucoma sets in.

Breakthrough work by researchers at the Indian Institute of Science (IISc) here has now resulted in the discovery of yet another mutant gene which has been linked to the development of MSP in two known cases in Karnataka.

The two children, from different consanguineous families, had been brought to an eye clinic in Bengaluru where doctors had diagnosed them as classic MSP cases.

However, at the same time, a genetic analysis showed that they did not have any mutation in the previously identified genes which can cause this defect.

"This was the starting point of our research,” explained Professor Upendra Nongthomba of the IISc's Department of Molecular Reproduction, Development and Genetics (MRDG).

After whole genome sequencing of the affected children and functional studies using zebrafish as a model system, and Crispr-Cas9 technology to "knockout" and "knockdown" genes in the fish, the scientists identified that mutation in the WDR8 gene is responsible for the decreased eye and lens size.

The scientists then made humanised fish, where the human counterpart of the WDR8 gene (normal and mutated gene sequence) was expressed in zebrafish to show that the gene was indeed responsible for producing the relevant “phenotype”.

Phenotype is a description of a person’s physical characteristics, like eye colour and height.

“The WDR8 gene was not previously known to cause this eye defect,” Professor Nongthomba said, explaining the discovery as a “Eureka” moment.

Study co-author Professor Arun Kumar, a geneticist with MRDG, added: “The discovery of the new causative gene means that we can find cases early and treat them early."

Already, by examining the Exome Aggregation Consortium, a database of over 60,700 sequences from around the world, primarily Southeast Asia, the scientists have found three additional cases that had never been formally identified with the defect.

IISc PhD student M Madhangi was the lead author of this study.