Epileptic encephalopathy linked to protein trafficking gene

November 28, 2016
A neuron in culture was transduced with a virus that expresses a green fluorescent protein and an inhibitory RNA that causes loss of the DENND5A protein. The neurons where then stained with a marker of neuronal processes in red. Credit: Peter McPherson Lab, Montreal Neurological Institute

Researchers have linked a debilitating neurological disease in children to mutations in a gene that regulates neuronal development through control of protein movement within neuronal cells.

The scientists from the Montreal Neurological Institute and Hospital at McGill University, led by Peter McPherson, along with collaborators in Saudi Arabia, Jordan, Germany, and at SickKids Hospital and the University of Toronto, have discovered that a severe form of epileptic encephalopathy is caused by recessive loss-of-function mutations in the gene DENND5A. Their findings were published in the American Journal of Human Genetics on Nov. 17.

Epileptic encephalopathy is a rare but devastating sub-form of epilepsy that results in severe mental and physical disabilities in children from birth. It is often caused by improper development of the brain. Individuals with epileptic encephalopathy caused by mutations in DENND5A present with serious anomalies in brain structure along with calcifications in the brain and altered facial features.

Researchers performed whole exome sequencing on three children with epileptic encephalopathy from two families, one from Saudi Arabia and another from Jordan. Both families were consanguineous, meaning the parents were related to each other. This greatly increases the chance that that are recessive and that cause no harm to the parents are expressed in the children. The whole exome sequencing, along with extensive and complex genetic analysis, revealed that in DENND5A were responsible for the disease, with the Saudi family and the Jordanian family having different mutations but in the same DENND5A gene. They found that mutations in DENND5A lead to a lack of the DENND5A protein, resulting in underdevelopment of the central nervous system. The protein expressed from the DENND5A gene is present at highest levels in the nervous system especially while the brain is developing, corroborating the evidence that mutations in the gene cause epileptic encephalopathy.

The researchers discovered that the DENND5A protein controls the movement of receptors for key developmental factors called neurotrophins. Disruption of DENND5A function leads to altered levels of these receptors, which could explain why loss of DENND5A leads to the severe neurological developmental defects in the patients.

Epilepsy affects approximately three per cent of the world population, and epileptic encephalopathy is a rare sub-form of the disease. It is difficult to say how many children with epileptic encephalopathy have the DENND5A mutations, but now that the gene has been identified as a cause, researchers around the world can begin to test patients for mutations in this gene.

This finding also improves our understanding of . The observation that loss-of-function mutations in DENND5A causes epileptic encephalopathy suggests that DENND5A protein controls membrane trafficking pathways critical for normal neuronal development and strengthens the argument that protein trafficking processes in cells are critical for normal neuronal development and function.

"Our study demonstrates the importance of membrane trafficking in neuronal development and it provides a new pathophysiological mechanism for this disease type. This will allow physicians around the world to test if in DENND5A are causing the disease in their patients, and also to provide genetic counselling for affected families," says Dr. Chanshuai Han, the lead author on the study.

Explore further: Deep dive into NMDA receptor variation and link to epilepsy, ID

More information: Chanshuai Han et al. Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A, The American Journal of Human Genetics (2016). DOI: 10.1016/j.ajhg.2016.10.006

Related Stories

Deep dive into NMDA receptor variation and link to epilepsy, ID

November 10, 2016
The study of human genetics has often focused on mutations that cause disease. When it comes to genetic variations in healthy people, scientists knew they were out there, but didn't have a full picture of their extent.

Researchers identify gene linked with early epilepsy

March 11, 2015
Certain types of early-onset epilepsy are caused by previously unknown mutations of a potassium channel gene, KCNA2. The mutations disrupt the electrical balance in the brain in two ways. In some patients, the flow of potassium ...

Researchers unravel mysteries of SCN8A mutation in epilepsy

December 6, 2015
Three studies presented at the American Epilepsy Society's (AES) 69th Annual Meeting explore the effects of mutations in the SCN8A gene, thought to underlie early infantile epileptic encephalopathy (EIEE) and other neurological ...

Finding a genetic cause for severe childhood epilepsies

May 27, 2013
(Medical Xpress)—A large scientific study has discovered new genes causing severe seizure disorders that begin in babies and early childhood. The finding will lead to new tests to diagnose these conditions and promises ...

Unraveling the genetic basis of sudden unexpected death in epilepsy

December 7, 2015
The leading cause of epilepsy-related death is a poorly understood phenomenon known as sudden unexpected death in epilepsy (SUDEP). The risk factors and causes of SUDEP remain unclear but researchers have proposed explanations ...

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 ...

Recommended for you

A rogue gene is causing seizures in babies—here's how scientists wants to stop it

July 26, 2017
Two rare diseases caused by a malfunctioning gene that triggers seizures or involuntary movements in children as early as a few days old have left scientists searching for answers and better treatment options.

Scientists provide insight into genetic basis of neuropsychiatric disorders

July 21, 2017
A study by scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) is providing insight into the genetic basis of neuropsychiatric disorders. In this research, the first mouse model of a mutation ...

Scientists identify new way cells turn off genes

July 19, 2017
Cells have more than one trick up their sleeve for controlling certain genes that regulate fetal growth and development.

South Asian genomes could be boon for disease research, scientists say

July 18, 2017
The Indian subcontinent's massive population is nearing 1.5 billion according to recent accounts. But that population is far from monolithic; it's made up of nearly 5,000 well-defined sub-groups, making the region one of ...

Mutant yeast reveals details of the aberrant genomic machinery of children's high-grade gliomas

July 18, 2017
St. Jude Children's Research Hospital biologists have used engineered yeast cells to discover how a mutation that is frequently found in pediatric brain tumor high-grade glioma triggers a cascade of genomic malfunctions.

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 ...

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.