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Developmental Biology - Brain Development

How A Defective Gene May Cause Autism

A defect in the MEF2C gene can cause one form of autism...

A collaboration between scientists at the Medical University of South Carolina and clinicians at the Greenwood Genetic Center has yielded new findings about how a particular gene might regulate brain development.

The paper published in Biological Psychiatry showcases how researchers connected problems in mice with a defective copy of the gene MEF2C — to issues suffered by patients seen at the Greenwood Genetic Center having a defective copy of that same gene.
Patients having a rare form of autism called haploinsufficiency syndrome, have only one functioning of two MEF2C genes in each cell of their body, resulting in an inability to use language, epilepsy, repetitive muscle movements, low muscle tone and breathing problems.

The remaining non-mutated copy of the MEF2C gene is less powerful and unable to regulate normal brain development, according to Cowan, chairman of the Department of Neuroscience. Cowan's lab conducted the study and believes these research results raise prospects for treatment.
"Individuals have half the MEF2C as is needed. From a therapy standpoint, I think this opens a lot of interesting doors. We can think about ways to introduce more MEF2C into the brain during critical periods of brain development."

Christopher Cowan PhD, Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolin, USA.

It's not yet clear when interventions could be effective or if there is a developmental point of no return, explains Cowan. However, he notes that most children with this syndrome experience seizures by 20 months old, which could be seen as a trigger for genetic testing - followed by potential treatment.
Cowan had studied MEF2C for more than a decade. Previously finding the MEF2 family is involved in synaptic pruning — the process by which the brain becomes more efficient as it prunes away redundant or irrelevant synaptic connections.

This process occurs through young adulthood, but is most active in preschool and elementary school years. He also observed a connection to fragile X syndrome, the most common inherited form of autism.

When Cowan moved to South Carolina in 2016, he gave a talk at the Greenwood Genetic Center about his latest research findings, including MEF2C. The paper's joint lead authors, Adam Harrington, postdoctoral scholar, and Catherine Bridges a MUSC medical scientist in training, both presented on MEF2C in mice at the same conference. Steve Skinner MD, Director of the Greenwood Genetic Center, also attended and realized he'd just seen a patient with this gene dysfunction. Cowan and his team connected over their mutual interests.

A Collaboration Blossoms

Cowan and Skinner first created a mouse model of MEF2C haploinsufficiency syndrome, after scouring the scientific literature looking for gene mutations already identified. They soon realized nearly all mutations were in the DNA binding region affecting the highly conserved protein MEF2C.
Highly conserved protein regions have barely changed through millions of years of evolution - they remain nearly identical whether in yeast, flies or humans, strongly suggesting they serve a very important function.

MEF2C protein is a transcription factor within the nucleus of the cell. It binds to DNA and turns on hundreds of genes, explains Cowan. These genes must be activated at just the right time for neurons to mature, form appropriate connections and adapt in response to experiences. Mutations occurring in this "hub" gene suggest they might be caused in MEF2C binding to DNA.
The mouse model of MEF2C Haploinsufficiency given one good copy and one inactive copy of MEF2C, shows the same social deficits, hyperactivity, repetitive behavior and a significant reduction in ultrasonic vocalizations.

"We don't know for sure what mouse ultrasonic vocalization means to another mouse, but they generate them in social contexts," says Cowan. Researchers consider vocalizations a "species-appropriate communication mode," and this communication problem in mice, he explains, mirrors the communication problems of children in the human study.

When the team analyzed the genes in the mouse brains that were abnormally expressed and compared them to the human genome, two areas pinged. The first was excitatory neurons, and the second was the microglia, what Cowan calls "the brain's resident immune cell." Microglia eat up dead cells after an injury or a stroke and also physically remove synaptic material to help with pruning during normal brain development.
When the scientists then removed MEF2C from just the neuronal cells or just the microglia, different subsets of autism-like behaviors were produced.

"For the field, I think it's important because it's starting to help us appreciate that neurodevelopmental disorders are probably a convergence of dysfunction or altered development of multiple different cell types. This has treatment implications as well because you can't just target the neuronal population. You can't just target microglia. You're probably going to have to think about the cluster of different cooperating cell types in the brain that lead to a typically functioning brain,"' says Cowan.

Research continues with cooperation from families across the world whose children have the disorder. A relatively small group, the internet and social media have given patients with rare disorders the opportunity to combine forces in seeking answers and even charting a path for research, says Skinner.

For example, parents of children with Rett syndrome, another rare neurodevelopmental disorder, pointed out how their children often suffered with gallbladder disease at a young age. Yet, nowhere was this disorder described in the scientific literature, only the parents saw this common thread amongst their children. As parents began pressing for confirmation, researchers began looking at their questions and found connections parents had intuited.
"Parents can drive research to find treatments for their children."

Steven A. Skinner MD; Director, Greenwood Genetic Center, Greenwood, South Carolina.

The parents of children with MEF2C haploinsufficiency syndrome deeply appreciate the opportunity to talk to a researcher like Cowan, he adds. The online support and information group, which consists of a few hundred MEF2C families across the world, is participating in future research, too. The research team recruited a Clemson University graduate student to develop a questionnaire to send to these families. It covers topics like when and which symptoms appeared — and which treatments they have tried. A cooperative effort with MUSC which has been rewarding.
"It's been a very collegial and collaborative relationship. Dr. Cowan has been very receptive to fielding questions from us, patients and families. He feels the relationship with families has been helpful in providing real-world context for his lab's work.

"Right in our own backyard, in South Carolina, are tools and research capabilities to attack really complex problems in biology. It's been a really great collaboration."

Steven A. Skinner MD.

Microdeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C haploinsufficiency syndrome (MCHS). MEF2C hypofunction in neurons is presumed to underlie most of the symptoms of MCHS. However, it is unclear in which cell populations MEF2C functions to regulate neurotypical development.

Multiple biochemical, molecular, electrophysiological, behavioral, and transgenic mouse approaches were used to characterize MCHS-relevant synaptic, behavioral, and gene expression changes in mouse models of MCHS.

We showed that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding–deficient global Mef2c heterozygous mice ( Mef2c-Het) displayed numerous MCHS-related behaviors, including autism-related behaviors, changes in cortical gene expression, and deficits in cortical excitatory synaptic transmission. We detected hundreds of dysregulated genes in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory neuron genes. In addition, we observed an enrichment of upregulated microglial genes, but this was not due to neuroinflammation in the Mef2c-Het cortex. Importantly, conditional Mef2c heterozygosity in forebrain excitatory neurons reproduced a subset of the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduced social deficits and repetitive behavior.

Taken together, our findings show that mutations found in individuals with MCHS disrupt the DNA-binding function of MEF2C, and DNA binding–deficient Mef2c global heterozygous mice display numerous MCHS-related phenotypes, including excitatory neuron and microglia gene expression changes. Our findings suggest that MEF2C regulates typical brain development and function through multiple cell types, including excitatory neuronal and neuroimmune populations.

Adam J. Harrington, Catherine M. Bridges, Stefano Berto, Kayla Blankenship, Jennifer Y. Cho, Ahlem Assali, Benjamin M. Siemsen, Hannah W. Moore, Evgeny Tsvetkov, Acadia Thielking, Genevieve Konopka, David B. Everman, Michael D. Scofield, Steven A. Skinner and Christopher W. Cowan.

About MUSC
Founded in 1824 in Charleston, MUSC is the oldest medical school in the South, as well as the state's only integrated, academic health sciences center with a unique charge to serve the state through education, research and patient care. Each year, MUSC educates and trains more than 3,000 students and 700 residents in six colleges: Dental Medicine, Graduate Studies, Health Professions, Medicine, Nursing and Pharmacy. The state's leader in obtaining biomedical research funds, in fiscal year 2018, MUSC set a new high, bringing in more than $276.5 million. For information on academic programs, visit http://musc.edu.As the clinical health system of the Medical University of South Carolina, MUSC Health is dedicated to delivering the highest quality patient care available, while training generations of competent, compassionate health care providers to serve the people of South Carolina and beyond. Comprising some 1,600 beds, more than 100 outreach sites, the MUSC College of Medicine, the physicians' practice plan, and nearly 275 telehealth locations, MUSC Health owns and operates eight hospitals situated in Charleston, Chester, Florence, Lancaster and Marion counties. In 2018, for the fourth consecutive year, U.S. News & World Report named MUSC Health the number one hospital in South Carolina. To learn more about clinical patient services, visit http://muschealth.org. MUSC and its affiliates have collective annual budgets of $3 billion. The more than 17,000 MUSC team members include world-class faculty, physicians, specialty providers and scientists who deliver groundbreaking education, research, technology and patient care.

About the SCTR Institute
The South Carolina Clinical and Translational Research (SCTR) Institute is the catalyst for changing the culture of biomedical research, facilitating sharing of resources and expertise and streamlining research-related processes to bring about large-scale change in the clinical and translational research efforts in South Carolina. Our vision is to improve health outcomes and quality of life for the population through discoveries translated into evidence-based practice. To learn more, visit https://research.musc.edu/resources/sctr

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May 21 2020   Fetal Timeline   Maternal Timeline   News

Christopher Cowan noticed that most children with MEF2C syndrome experienced seizures by age 20 months, suggesting genetic testing was needed. Hopefully there will be potential for early treatment.
DNA image — public domain.

Phospholid by Wikipedia