IISc researchers discover unknown gene creating smaller eye lenses


The combination of a species of freshwater fish, two children from rural areas and six years of grueling investigative work 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 lens is smaller than normal that inevitably leads to second-stage glaucoma in children if left untreated. It worries the researchers because all the genetic factors at the origin of this defect are not known.

The condition has been described in different ethnic groups since 1901, mainly in Asia and North Africa. The exact incidence rate is not known, but scientific literature postulates that 1.2% of the 5.6 million Indian children who present with lens abnormalities each year suffer from microspherophakia.

While scientists know of three mutated genes in the human body that can cause this eye abnormality, the lack of information means that thousands of children around the world go undetected until glaucoma sets in.

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

The two children, from different consanguineous families, were taken to an eye clinic in Bengaluru where doctors diagnosed them as classic cases of PSD.

However, at the same time, genetic analysis showed that they did not have any mutations in previously identified genes that could cause this defect.

“This was the starting point for our research,” explained Professor Upendra Nongthomba from the Department of Molecular Reproduction, Development and Genetics (MRDG) at IISc.

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

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

Phenotype is a description of a person’s physical characteristics, such as eye color and height.

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

Study co-author Prof Arun Kumar, geneticist at MRDG, added: “The discovery of the new causative gene means we can find cases early and treat them early.”

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

The IISc doctoral student, M Madhangi, was the lead author of this study.


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