Rare Disease Report

Mutations in New Gene Identified as Cause of Childhood Blindness

AUGUST 08, 2018
Krista Rossi
Investigators from the University of Geneva (UNIGE), Switzerland—in collaboration with scientists from Pakistan and the United States—have identified pathogenic mutations in a new gene, MARK3, which they found to be responsible for pediatric blindness caused by an unknown recessive genetic eye disorder.

Recessive genetic disorders are triggered by a mutation on both copies of the gene, as is seen with cystic fibrosis. In order for the disorder to fall into this category it must affect at least 2 children from the same family and the children’s parents must be in good health.

In the study, published in Human Molecular Genetics, the research team sought to uncover the molecular causes of developmental eye defects in consanguineous populations—in which recessive eye disorders are frequently seen—by identifying recessive causative genes.

"In our attempts to uncover new recessive genetic disorders, we looked at families where there was consanguineous marriage and where both parents carried one copy the mutant gene and passed it on to the child," said Stylianos Antonarakis, a professor Emeritus in UNIGE's Faculty of Medicine, in a recent statement. “We found that the disorder was present in children from consanguineous parents. As a result, we hypothesized that it was a recessive genetic disorder.”

A total of 200 Pakistani families were selected to be included in the research program. For their study, the investigators focused on a Pakistani consanguineous family in which 3 children were affected with congenital vision loss and progressive eye degeneration and 2 children were healthy. The investigators sequenced the genomes of every member of the family.

 “The aim was to see which gene had mutations on 2 copies in the affected children, on 1 copy in the parents, and 1 or 0 copies in the normal siblings,” Muhammad Ansar, the lead researcher in the department of Genetic Medicine and Development at UNIGE, added. According to the recent news release, bio-informatic analysis and genetic segregation led the investigators to conclude that the MARK3 gene was responsible for the recessive disorder.

The team then set out to confirm their findings by testing to see if a similar mutation in fruit flies (drosophilae) would result in the same eye defects. To do this, the UNIGE team partnered up with investigators at Houston’s Baylor College of Medicine. Since drosophilae often highly conserve MARK3 gene, the team decided to knock down the MARK3 homologue, par-1, in the eye during development. Doing this resulted in a significant reduction in eye size, a severe loss of photoreceptors, and loss of vision based on electroretinogram (ERG) recordings. Expression of the mutation (par-1 p.Arg792Gly) equivalent to the MARK3 variant identified in human patients was found to also encourage the loss of eye tissue and a reduction in ERG signals.

These findings further supported those observed in human patients, that the MARK3 mutation results in loss of function. As such, the investigators concluded that the identified mutation in MARK3 establishes a new gene-disease link. The discovery of the MARK3 mutation allows for accurate diagnosis of a new recessive disorder.

With this data, investigators can now concentrate on gleaning a better understanding of the mechanisms behind the disorder in an attempt to develop a treatment, according to Dr Antonarakis. Since performing a quick and inexpensive test on individuals in the same extended family is also feasible, gene carriers can also avoid marriages with other carriers of the pathogenic gene mutation in order to prevent passage of the genetic mutation (blindness) to children.

"Our collaboration with Pakistan helped us identify about additional 30 genes that are potentially responsible for recessive genetic disorders,” conclude the Geneva researchers. “We are currently refining the analyses so that, little by little, we can reduce the total number of 16,000 genes whose mutations and disorders are yet to be discovered.”

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