Intellectual disabilities caused by protein defect

September 4, 2017, Radboud University

Intellectual disabilities are often caused by a mutation that damages a gene, preventing the associated protein from functioning properly. However, a mutation can also change the function of a gene. As a result, the gene in question acts in a completely different way. Researchers from Radboudumc discovered this mechanism in fifteen genes playing a role in the development of intellectual disabilities. Their research results published in the American Journal of Human Genetics on 31 August 2017 show that these changes in function play a more prominent role than previously thought.

Genes are responsible for protein production in cells. A common cause of intellectual is a de novo mutation (i.e. a mutation present in a child, but not in its parents) damaging a gene so severely that it is no longer able to produce functional proteins. The resulting protein defect will cause illness. In a number of disease-related genes, it is shown that a de novo mutation does not eliminate the gene, but probably alters its . These are only located on specific parts of the gene.

Change in function

In order to find out how often this mechanism is involved, researchers from Radboudumc have combined the gene mutations in Dutch patients with a large international database comprising de novo mutations in patients. This research project was led by geneticist Christian Gilissen. "With our method, we were able to detect genes in which mutations not so much eliminate as affect the gene in another way. We found fifteen genes in which mutations cluster closely together, twelve of which being associated with developmental disorders. We also found three new genes that are likely to play a role in the development of intellectual disabilities as well", according to Gilissen.

Interactions

The de novo mutations that were found only change a very small part of a protein. The function of the remains largely, but not entirely the same. Gilissen says: "The mutations are more likely to affect superficial parts of the proteins. These disturb interactions with other proteins and cause problems. Although mutations eliminating genes were often thought to be the main cause of intellectual disabilities, mutations altering the function of genes are now shown to be an important factor as well. That is a surprising finding."

Clustering mutations

Why are the de novo mutations that were found specifically clustered? Gilissen says: "There can be several explanations for that. Firstly, these genes show little natural variation. If such a gene is completely eliminated, a person may not be born. Only mutations located on very specific parts of the gene are viable. Consequently, only these mutations can be found. Another explanation can be that the mutations provide growth benefits to the sperm in which they develop. In that case, only these mutations would be able to survive."

New possibilities

The three newly-discovered playing a role in the development of intellectual disabilities provide new diagnostic possibilities for patients. Gillissen says: "It is important that we have discovered a mechanism that has not yet been a focus of study. We expect this mechanism to play a role in a much larger proportion of patients with ."

Explore further: Late-breaking mutations may play an important role in autism

More information: Stefan H. Lelieveld et al. Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes, The American Journal of Human Genetics (2017). DOI: 10.1016/j.ajhg.2017.08.004

Related Stories

Late-breaking mutations may play an important role in autism

July 17, 2017
A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital ...

Gene that causes intellectual disability when mutated finally identified

July 29, 2015
At least half of those with an intellectual disability across the world do not have a formal diagnosis. However, thanks to new DNA sequencing technology, along with the expertise and perseverance of University of Adelaide ...

Timing of mutation determines the outcome

June 30, 2017
A single genetic mutation can lead to completely different diseases, depending on the time and location at which the mutation occurs. This finding emerged from the PhD study conducted by Rocio Acuña-Hidalgo of Radboudumc. ...

Intellectual disability is frequently caused by non-hereditary genetic problems

April 18, 2011
Mutations in a group of genes associated with brain activity frequently cause intellectual disability, according to a study led by scientists affiliated with the University of Montreal and the research centre at the Centre ...

Novel genetic mutations may arise during early embryonic development

June 5, 2015
Until now, de novo genetic mutations, alterations in a gene found for the first time in one family member, were believed to be mainly the result of new mutations in the sperm or eggs (germline) of one of the parents and passed ...

Recommended for you

Discovery of the 'pioneer' that opens the genome

January 23, 2018
Our genome contains all the information necessary to form a complete human being. This information, encoded in the genome's DNA, stretches over one to two metres long but still manages to squeeze into a cell about 100 times ...

Researchers identify gene responsible for mesenchymal stem cells' stem-ness'

January 22, 2018
Many doctors, researchers and patients are eager to take advantage of the promise of stem cell therapies to heal damaged tissues and replace dysfunctional cells. Hundreds of ongoing clinical trials are currently delivering ...

Genes contribute to biological motion perception and its covariation with autistic traits

January 22, 2018
Humans can readily perceive and recognize the movements of a living creature, based solely on a few point-lights tracking the motion of the major joints. Such exquisite sensitivity to biological motion (BM) signals is essential ...

Peers' genes may help friends stay in school, new study finds

January 18, 2018
While there's scientific evidence to suggest that your genes have something to do with how far you'll go in school, new research by a team from Stanford and elsewhere says the DNA of your classmates also plays a role.

Two new breast cancer genes emerge from Lynch syndrome gene study

January 18, 2018
Researchers at Columbia University Irving Medical Center and NewYork-Presbyterian have identified two new breast cancer genes. Having one of the genes—MSH6 and PMS2—approximately doubles a woman's risk of developing breast ...

A centuries-old math equation used to solve a modern-day genetics challenge

January 18, 2018
Researchers developed a new mathematical tool to validate and improve methods used by medical professionals to interpret results from clinical genetic tests. The work was published this month in Genetics in Medicine.

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.