Nav: Home

Finding a cause of neurodevelopmental disorders

July 30, 2019

LA JOLLA--(July 30, 2019) Neurodevelopmental disorders arising from rare genetic mutations can cause atypical cognitive function, intellectual disability, and developmental delays, yet it is unclear why and how this happens. Scientists suspected a mutation in a complex of proteins could be the culprit for a group of rare genetic disorders and, now, Salk Institute researchers have identified the molecular mechanism linking this mutation with abnormal nervous system development. The team's findings, published in Molecular Cell on July 30, 2019, bring researchers one step closer to understanding neurodevelopmental disorders, such as Nicolaides-Baraitser syndrome and others.

"For the first time, we have been able to characterize the mechanism of a known gene mutation implicated in neurodevelopmental disorders," says Assistant Professor Diana Hargreaves, senior author and holder of the Richard Heyman and Anne Daigle Endowed Developmental Chair.

The root cause has to do with a complex of proteins called the SWI/SNF complex, which is involved in DNA regulation, and, when mutated, is associated with Nicolaides-Baraitser syndrome, Coffin-Siris syndrome, autism and even some cancers. These complexes repackage and reshape the DNA in the nucleus to either enable or prevent access to genes. And yet, scientists do not know how mutations in individual subunits of the SWI/SNF complex affect its function.

"We sought to understand how a single mutation in the SMARCA2 subunit affected brain development," says Fangjian Gao, the paper's first author and a postdoctoral fellow at Salk. "We expected to see some effect on the neurodevelopmental pathways, but we were not sure how, specifically."

The scientists turned to cell cultures in a dish to model growth patterns in afflicted brain cells versus normal brain cells. They used the gene-editing technique CRISPR to mimic the SMARCA2 mutation observed in Nicolaides-Baraitser syndrome. Notably, the researchers found that healthy cells had minimal SMARCA2 activity. The cells with the mutation, however, had a dramatic increase in SMARCA2 activity and a significantly impaired ability to generate precursors to neurons, called neural progenitor cells. In this highly activated state, SMARCA2 affected the function of the normal SWI/SNF complex. This led to a domino effect with changes in gene expression resulting in abnormal brain development.

"By better understanding this mutation in SMARCA2, we have tapped into what looks like a core developmental process that could be perturbed in disease states such as autism or even cancer," says Hargreaves.
-end-
Other authors included Nicholas J. Elliott, Josephine Ho and Maxim N. Shokhirev of Salk, along with Alexzander Sharp of the University of California San Diego.

The work was funded by the Helmsley Trust, the National Institutes of Health (9R35 GM128943-01 and R00 CA184043-03) and the V Foundation for Cancer Research (V2016-006).

About the Salk Institute for Biological Studies:

Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.

Salk Institute

Related Science Articles:

PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.
AAAS and March for Science partner to uphold science
AAAS, the world's largest general scientific organization, announced Thursday that it will partner with the March for Science, a nonpartisan set of activities that aim to promote science education and the use of scientific evidence to inform policy.
Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.
Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.
Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.
More Science News and Science Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Erasing The Stigma
Many of us either cope with mental illness or know someone who does. But we still have a hard time talking about it. This hour, TED speakers explore ways to push past — and even erase — the stigma. Guests include musician and comedian Jordan Raskopoulos, neuroscientist and psychiatrist Thomas Insel, psychiatrist Dixon Chibanda, anxiety and depression researcher Olivia Remes, and entrepreneur Sangu Delle.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...