Newly Described Intellectual Disability Syndrome Caused by Damage to Single Gene

Scientists have discovered that the gene for transcription factor BCL11A is responsible for a previously unidentified intellectual disability and have identified a mechanism by which loss-of-function BCL11A mutations can lead to cognitive disability. The findings could lead to new targeted therapies and diagnostic tests for this disorder.

Scientists at the Wellcome Trust Sanger Institute (Cambridgeshire, UK) and Max Planck Institute for Psycholinguistics (Netherlands & Germany) showed that if one of a person’s two BCL11A alleles is damaged then they will have the newly described intellectual disability. Using cultured human cells and a mouse model, the team found that two healthy copies of BCL11A are needed to make enough BCL11A protein for brain cells to develop normally and function at capacity.

Nearly 3% of the human population has some form of learning disability. These disabilities are poorly understood as they can be caused by different genetic and/or other factors; the way conditions present in patients also varies. Sanger Institute’s Deciphering Developmental Disorders research program has found many new genes associated with intellectual disability. However, relatively little is known about how these genes work as each genetic cause is so rare. By exploring the mechanism in mice, the team has now been able to show, for the first time, specific genetic impact on development.

The team, led by Dr. Darren Logan and Prof. Simon Fisher, worked with 9 patients who have an intellectual disability. They found that these people share the same genetic profile and symptoms that they now define as a new clinical syndrome. Each patient also had the same unusual blood profile, which could be used to help diagnose patients in the future.

“We worked with patients, studied human cells, and made a mouse model to translate research from the gene discovery phase into understanding a cause of intellectual disability. We’ve shown that the BCL11A gene does cause an intellectual disability syndrome. It’s an excellent example of gene discovery by patient DNA sequencing paired with experimental investigation to prove a link between gene and outcome that is backed up by cellular and animal studies. We plan to follow this model on an even larger scale in the future, to test the role of many other genes associated with intellectual disability,” said Dr. Logan, lead researcher from Wellcome Trust Sanger Institute.

The research also revealed that mutated BCL11A influences many other genes important for brain development and function. Prof. Fisher, director of Max Planck Institute for Psycholinguistics, said: “We were interested to find severe problems with speech and language development as a consistent feature of the syndrome caused by BCL11A mutations. Studies like ours are beginning to reveal intriguing connections between the biological causes of intellectual disability and disorders of spoken language. And although BCL11A mutations are themselves rare, the gene belongs to a bigger network of genes that are crucial for building a healthy brain, and so it can provide much broader insights into the basis of human cognition and how this might go wrong during development.”

“The contribution of patients and their families to this study was essential for us to understand how a mutation in BCL11A affects them as a group. This is a newly recognized condition so it is important we continue patient studies. We will use experimental resources of cells and mouse models to further investigate how the mutations are influencing other genes, and find potential drug targets,” Dr. Cristina Dias, clinical geneticist at Dr. Logan’s laboratory.

The study, by Dias C, Estruch S et al, was published July 21, 2016, in the American Journal of Human Genetics.

Related Links:
Wellcome Trust Sanger Institute
Max Planck Institute for Psycholinguistics