Blindness gene discovered

July 23, 2018, University of Geneva
Blindness gene discovered
Top: the eyes of two children affected by the recessive genetic disorder caused by MARK3 mutations. Bottom left: the eye of a healthy drosophila. Bottom right: the eye of a drosophila affected by the MARK3 mutation. Credit: UNIGE

The human genome is made up of 20,000 genes, all of which may cause disease. At present, 4,141 genes have been identified as being responsible for genetic abnormalities, leaving around 16,000 genes with unknown implication in disease. Researchers from the University of Geneva (UNIGE), Switzerland, working in collaboration with scientists from Pakistan and the USA, have investigated a recessive genetic disorder that prevents the eyes from developing and results in childhood blindness.

After analysing the genomes of each member of a consanguineous family with affected children, the geneticists pinpointed pathogenic mutations in a new gene, MARK3, as the cause. They subsequently confirmed their findings, published in the journal Human Molecular Genetics, by modifying the homologous gene in drosophila flies, which resulted in abnormal eye development and blindness. The identification of the MARK3-related disease will help researchers to understand the mechanism of the disease, provide diagnostic services, and initiate efforts for a personalized treatment.

Monogenic genetic disorders fall into two main categories: the first – so-called dominant disorders –only need one copy of the gene to be mutated to cause disorders such as Huntington's disease. The second – recessive disorders – are triggered by a mutation on both copies of the gene, as is the case with cystic fibrosis. "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 and passed it on to the child," explains Stylianos Antonarakis, a professor Emeritus in UNIGE's Faculty of Medicine. Supported by the the ProVisu Foundation of Geneva, the Geneva-based geneticists then joined forces with Liaquat University in Pakistan, a country where over 50 percent of marriages take place between close relatives (usually first cousins).

An unknown disorder that destroys eyesight

The geneticists directed their interest at an unknown illness that prevents the eyes from developing properly and gradually destroys them. "We found that the disorder was present in children from consanguineous parents. As a result, we hypothesised that it was a recessive genetic disorder," continues professor Antonarakis. For a disorder to fall into this category, it must affect at least two children from the same family (regardless of their sex) and the parents must be in good health.

Two hundred Pakistani families that fulfilled these criteria were selected for the research programme. "We started by sequencing the genomes of every member of a family that had three children with the genetic abnormality and two healthy children. The aim was to see which gene had mutations on two copies in the affected children, on one copy in the parents, and one or zero copies in the normal siblings," says Muhammad Ansar, a researcher in the Department of Genetic Medicine and Development at UNIGE. After carrying out a bio-informatic analysis and genetic segregation to look for the mutations of each gene in the healthy and affected children and their parents, the scientists isolated the MARK3 gene as responsible for the recessive disorder.

Confirming the result with drosophilae

"To confirm whether MARK3 really was the gene responsible for the blindness, we checked to see if a similar mutation in drosophilae led to the same eye abnormalities," says Ansar. The UNIGE researchers have collaborated with experts at Houston's Baylor College of Medicine, to genetically modify drosophilae by introducing the mutation of two copies in the MARK3 gene of the flies. The result was that the flies had undeveloped eyes, and they were blind very similarly to the affected children in the Pakistani family. These results provided a validation of the the research findings in human patients.

This discovery means that a new recessive disorder can be accurately diagnosed. "We can now concentrate on studying the mechanisms behind the disorder with the aim of finding a treatment," says Antonarakis. It is also possible to perform a quick and inexpensive test on people in the same extended family to determine whether or not they will pass on the mutant gene for this eye disorder to their children and, in some cases, so they can avoid marriage among carriers of the pathogenic gene mutation.

"Our collaboration with Pakistan helped us identify about additional 30 that are potentially responsible for recessive genetic disorders. 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," conclude the Geneva researchers.

Explore further: A syndrome combining intellectual disability, epilepsy and hypotonia results from the failure of a single gene

More information: Visual impairment and progressive phthisis bulbi caused by recessive pathogenic variant in MARK3 Human Molecular Genetics (2018).

Related Stories

A syndrome combining intellectual disability, epilepsy and hypotonia results from the failure of a single gene

March 17, 2016
Each gene variation has the potential to trigger specific defects. Among all genetic conditions, diseases recessive occur only when both the father and the mother are healthy carriers of the same defective gene which can ...

The Down's syndrome 'super genome'

January 19, 2018
Down's syndrome – also known as trisomy 21 – is a genetic disorder caused by an additional third chromosome 21. Although this genetic abnormality is found in one out of 700 births, only 20 percent of foetuses with trisomy ...

Mutations in gene TRAF7 are associated with a multisystem disorder

June 28, 2018
A group of seven patients presenting with a similar disorder of unknown origin now know of a possible genetic root of their condition. A team of researchers sequenced all the protein-coding genes in the patients' genomes ...

Researchers explore why humans don't purge lethal genetic disorders from the population

September 28, 2017
The human population carries around more deadly genetic diseases than would be expected based on a simple comparison of mutation rates and deaths of affected individuals. Carlos Eduardo Guerra Amorim of Stony Brook University ...

New brain development disorder identified by scientists

May 22, 2018
Researchers have identified a new inherited neurodevelopmental disease that causes slow growth, seizures and learning difficulties in humans.

The gene causing new brain disorder

March 23, 2018
Newly discovered gene mutations may help explain the cause of a disease that drastically impairs walking and thinking.

Recommended for you

Officials remove special rules for gene therapy experiments

August 16, 2018
U.S. health officials are eliminating special regulations for gene therapy experiments, saying that what was once exotic science is quickly becoming an established form of medical care with no extraordinary risks.

Genetic link discovered between circadian rhythms and mood disorders

August 15, 2018
Circadian rhythms are regular 24-hour variations in behaviour and activity that control many aspects of our lives, from hormone levels to sleeping and eating habits.

Ovarian cancer genetics unravelled

August 14, 2018
Patterns of genetic mutation in ovarian cancer are helping make sense of the disease, and could be used to personalise treatment in future.

New genome-editing strategy could lead to therapeutics

August 14, 2018
Researchers at UMass Medical School have developed a genome-editing strategy to correct disease-causing DNA mutations in mouse models of human genetic diseases, according to research published in the Aug. 18 edition of Nature ...

Study reveals broad 'genetic architectures' of traits and diseases

August 13, 2018
Scientists at Johns Hopkins Bloomberg School of Public Health have developed a powerful method for characterizing the broad patterns of genetic contributions to traits and diseases. The new method provides a "big picture" ...

Genetic tools uncover cause of childhood seizure disorder missed by other methods

August 13, 2018
Early childhood seizures result from a rare disease that begin in the first months of life. Researchers at University of Utah Health have developed high-tech tools to uncover the genetic cause of the most difficult to diagnose ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.