Neurological disease in mice and humans linked to an unlikely gene

February 1, 2018, Research Institute of Molecular Pathology
Composition of two mouse brain sections: left the brain of a healthy, juvenile mouse, right the equivalent without Vps15. Scientists linked this gene to defects in brain development in both mice and humans. Credit: Research Institute of Molecular Pathology

Screening for mutations influencing the migration of nerve cells in mice, scientists found a gene that plays a role in the transport of proteins within nerve cells. If less of the protein is present in the developing mouse, the scientists found that its brain showed severe defects. Investigating the situation in humans, they discovered that a mutation of the same gene underlies neural degeneration.

A database tool designed to link molecular biologists and clinical geneticists built the crucial bridge between laboratory and patient: a young man from an Eastern European country, suffering from the effects of a specific mutation as the only one among four siblings; degenerated nerves and brain, , spasticity, limits in his capacity to respond to stimuli or control his muscles and epilepsy are among a long list of symptoms that characterised his condition. He passed away at the age of 19.

For the scientists in the lab of David Keays at the Research Institute of Molecular Pathology (IMP) in Vienna, finding this patient was the last piece in a puzzle. Long before they reached out to clinical geneticists, they had started to screen mice for mutations with an impact on neural migration.

Developing vertebrate brains crucially depend on the correct generation, migration, differentiation and survival of . All of these are processes that require the orchestration of a high number of genes and their corresponding proteins, each of which can be disrupted in their normal role by mutations. Using biochemical methods to induce , the scientists identified Vps15 as one genes that was required for normal neuronal development, as they reported now in the journal Nature Neuroscience.

"It was an unlikely candidate," says Thomas Gstrein, first author of the paper. "There are more than 20,000 in humans. No one would have guessed that Vps15 was the culprit. You simply cannot make a brain without Vps15."

It was only through the broad screen – performed by collaborators at the University of Oxford—that the scientists picked up on this particular gene.

Subsequently, they characterized the brain development defects caused by the mutation in mice and studied the molecular mechanisms that involve Vps15 in the developing brain in detail – linking it to other proteins that play key roles in the organisation of the cytoskeleton. Once these mechanisms were understood, they turned to Genematcher, an interface that linked them to clinical geneticists and a patient with a mutation in the human homolog of Vps15 – the teenager with the neurodegenerative condition.

An examination of parents, siblings and the patient himself confirmed that the mutation in VPS15 – reducing the amount of the relevant in the – was indeed the cause of the observed neurodevelopmental defects. In concluding their paper, the point out that VPS15 may also play a role in other neurological conditions such as schizophrenia or autism – it calls for a closer look in future studies.

Explore further: CLOCK gene may hold answers to human brain evolution

More information: Thomas Gstrein et al. Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans, Nature Neuroscience (2018). DOI: 10.1038/s41593-017-0053-5

Related Stories

CLOCK gene may hold answers to human brain evolution

December 6, 2017
Scientists have long sought to unravel the molecular mysteries that make the human brain special: What processes drove its evolution through the millennia? Which genes are critical to cognitive development?

Microcephaly brain size linked to mutation in stem cell micro environment

August 9, 2017
New research highlights the significant role the surrounding environment of stem cells, known as the niche, might play in the brain size of babies with microcephaly.

How one gene contributes to two diseases

December 10, 2015
Although it is known that psychiatric disorders have a strong genetic component, untangling the web of genes contributing to each disease is a daunting task. Scientists have found hundreds of genes that are mutated in patients ...

Mutations in CWC27 result in a spectrum of developmental conditions

March 10, 2017
An international team of researchers has discovered that mutations in the human gene CWC27 result in a spectrum of clinical conditions that include retinal degeneration and problems with craniofacial and skeletal development. ...

New clues identified in childhood cancer syndrome

March 31, 2016
Children with the inherited cancer syndrome neurofibromatosis type 1 (NF1) are prone to developing brain and nerve tumors as well as myriad other medical problems, including autism, epilepsy and bone defects.

Discovery of gene effects on brain brings scientists closer to understanding rare developmental disorder

January 11, 2017
Scientists are closer to finding additional genetic causes for the rare developmental disorder Cornelia de Lange Syndrome after discovering the steps in brain development that may be affected in some patients.

Recommended for you

Receiving genetic information can change risk

December 11, 2018
Millions of people in the United States alone have submitted their DNA for analysis and received information that not only predicts their risk for disease but, it turns out, in some cases might also have influenced that risk, ...

HER2 mutations can cause treatment resistance in metastatic ER-positive breast cancer

December 11, 2018
Metastatic breast cancers treated with hormone therapy can become treatment-resistant when they acquire mutations in the human epidermal growth factor receptor 2 (HER2) that were not present in the original tumor, reports ...

How glial cells develop in the brain from neural precursor cells

December 11, 2018
Two types of cells are active in the brain: nerve cells and glial cells. Glial cells have long been regarded primarily as supportive cells, but researchers increasingly recognize that they play an active role in the communication ...

Big datasets pinpoint new regions to explore the genome for disease

December 10, 2018
Imagine rain falling on a square of sidewalk. While the raindrops appear to land randomly, over time a patch of sidewalk somehow remains dry. The emerging pattern suggests something special about this region. This analogy ...

Team seeks to create genetic map of worm's nervous system

December 10, 2018
How do you build a brain? What "rules" govern where neurons end up, how they connect to each other, and which functions they perform?

Genetic study of epilepsy points to potential new therapies

December 10, 2018
The largest study of its kind, led by international researchers including scientists at RCSI (Royal College of Surgeons in Ireland), has discovered 11 new genes associated with epilepsy.

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.