Genes Involved in Birth Defects May Also Lead to Mental Illness

6/25/2013

Gene mutations that lead to major birth defects may also cause subtle disruptions in the brain that contribute to psychiatric disorders such as schizophrenia, autism, and bipolar disorder, according to new research by UC San Francisco scientists.

By Jeffrey Norris

Over the past several years, researchers in the laboratory of psychiatrist Benjamin Cheyette, MD, PhD, have shown that mutations in a gene called Dact1 cause cell signaling networks to go awry during embryonic development. Researchers observed that mice with Dact1 mutations were born with a range of severe malformations, including some reminiscent of spina bifida in humans.
This new study was designed to explore whether Dact1 mutations exert more nuanced effects in the brain that may lead to mental illness. In doing so, Cheyette, John Rubenstein, MD, PhD, and colleagues in UCSF’s Nina Ireland Laboratory of Developmental Neurobiology used a genetic technique in adult mice to selectively delete the Dact1 protein only in interneurons, a group of brain cells that regulates activity in the cerebral cortex, including cognitive and sensory processes. Poor function of interneurons has been implicated in a range of psychiatric conditions.

Brain cells called interneurons, which regulate activity in the cerebral cortex, were
shown by UCSF researchers to form more complex branching patterns in normal
mice (left) in comparison to mice in which the gene encoding the protein Dact1
was knocked out (right).

As reported in the June 24 online issue of PLOS ONE, researchers found that the genetically altered interneurons appeared relatively normal and had managed to find their proper position in the brain’s circuitry during development. But the cells had significantly fewer synapses, the sites where communication with neighboring neurons takes place. In additional observations not included in the new paper, the team also noted that the cells’ dendrites – fine extensions that normally form bushy arbors studded with synapses – were poorly developed and sparsely branched.

“When you delete this gene function after initial, early development – just eliminating it in neurons after they’ve formed – they migrate to the right place and their numbers are correct, but their morphology is a little off,” Cheyette said. “And that’s very much in line with the kinds of pathology that people have been able to identify in psychiatric illness.

"Neurological illnesses tend to be focal, with lesions that you can identify or pathology you can see on an imaging study," Cheyette explained. "Psychiatric illnesses? Not so much. The differences are really subtle and hard to see.”

Key Gene's Role in Development of Human Nervous System

The Dact1 protein is part of a fundamental biological system known as the Wnt (pronounced “wint”) signaling pathway. Interactions among proteins in the Wnt pathway orchestrate many processes essential to life in animals as diverse as fruit flies, mice and humans, including the proper development of the immensely complex human nervous system from a single fertilized egg cell.

Benjamin Cheyette, MD, PhD

One way the Wnt pathway manages this task is by maintaining the “polarity” of cells during development, said Cheyette, “a process of sequestering, increasing the concentration of one set of proteins on one side of the cell and a different set of proteins on the other side of the cell.” Polarity is particularly important as precursor cells transform into nerve cells, Cheyette said, because neurons are “the most polarized cells in the body,” with specialized input and output zones that must wind up in the proper spots if the cells are to function normally.
Cheyette said his group is now conducting behavioral experiments with the mice analyzed in the new PLOS ONE paper and with genetically related mouse lines to test whether these mice have behavioral abnormalities in sociability, sensory perception, anxiety or motivation that resemble symptoms in major psychiatric disorders.

John Rubenstein, MD, PhD

He also hopes to collaborate with UCSF colleagues on follow-up experiments to determine whether the activity of neurons lacking Dact1 is impaired in addition to the structural flaws identified in the new study and prior published work from his lab.

Meanwhile, as-yet-unpublished findings from human genetics research conducted by Cheyette’s group suggest that individuals with autism are significantly more likely than healthy comparison subjects to carry mutations in a Wnt pathway gene called WNT1.

“Just because a gene plays an important role in the embryo doesn’t mean it isn’t also important in the brain later, and might be involved in psychiatric pathology,” said Cheyette. “When these genes are mutated, someone may look fine, develop fine and have no obvious medical problems at birth, but they may also develop autism in childhood or have a psychotic break in adulthood and develop schizophrenia.”

Rubenstein is the Nina Ireland Distinguished Professor in Child Psychiatry.
Additional study authors include postdoctoral scholars Xiaoyong Yang, PhD, Daniel Vogt, PhD, and Amelia Stanco, PhD, and graduate student and first author Annie Arguello. Yang and Stanco are supported by a postdoctoral training grant (T32) led by Judy Ford, PhD, to the UCSF Department of Psychiatry from the National Institute of Mental Health.

Arguello conducted this research while obtaining her PhD in the UCSF doctoral program in Biomedical Sciences (BMS), and was supported by the Initiative to Maximize Student Development Program of the National Institute of General Medicine, as well as by BMS, the UCSF Department of Psychiatry, and the Center for Neurobiology and Psychiatry led by Sam Barondes, MD, Jeanne and Sanford Robertson Endowed Chair in Neurobiology and Psychiatry.

Filmmakers to tackle Canadian Agent Orange scandal

Filmmakers to tackle Agent Orange scandal
Published Monday March 9th, 2009

A group of New York moviemakers will settle into the Fredericton region for the next few weeks to film what it calls "Canada's dirty secret" to a worldwide audience.

Filmmakers Danny Feighery and Gregg de Domenico and two colleagues arrive in Fredericton today to work on their documentary about the lingering effects of the spraying of Agent Orange and other toxic chemicals at Canadian Forces Base Gagetown.

They will remain until the April 1 deadline for the federal government's $20,000 ex-gratia compensation payments passes.

"It's such a bizarre story," said Feighery. "There's all these different qualifiers and rules and absurdities to it."

"The whole story seems to be pretty absurd. There's never been anything so massive in western civilization for a government to poison their own people on this scale."

He's personally invested in the story.

His grandfather was a member of the provost corps at CFB Gagetown - the precursor to the military police - so his mother Sharon grew up on the base, ate blueberries that had grown on the base and played there.

When his sister Theresa was born, she had spina bifida. It's a congenital defect of the spine, in which part of the spinal cord and the meninges are exposed through a gap in the backbone. The condition has been linked to exposure to Agent Orange and a whole host of other toxic chemicals that were sprayed on the base.

It wasn't until a family reunion last year in Nova Scotia where relatives talked about Agent Orange that Feighery's family began drawing possible links to his sister's spina bifida and exposure to toxic defoliants.

"No democracy has ever let half a million people be contaminated by a toxin and then never tell them about it and cover it up," he said.

De Domenico said the story deserves a wider audience.

"I'm curious about the story and I'd like to see somebody see this through to get some answers," he said. "I know, personally, I feel like - especially coming out of the Bush administration in the United States - we're all looking for some degree of accountability from our governments.

"I know I personally feel like I want to see transparency and I want to see fairness. I want to know we're not being taken advantage of by corporate interests."

They plan to delve into the involvement of chemical companies, the military and the government.

"We want to go further, looking into the factfinder's mission, the results of the factfinder's mission, how that affected Veterans Affairs and the compensation packages. Then straight into the compensation packages ending April 1 and where does everyone go from there," de Domenico said.

Veterans Affairs Minister Greg Thompson has said the April 1 deadline isn't absolute and if a late application is received, it will be considered.

Payments are also considered for primary caregivers of qualifying individuals who died on or after Feb. 6, 2006, the date the federal Conservative government took office.

Thankfully, he said, many people in the region have taken up the challenge of doing the research.

He just hopes to do them justice on the big screen.

"We're very much doing our best to tell their story."

"There's only so many times you can sit with them and hold their hands while they're crying, saying they feel left in the cold. I want to feel like we can get the word out and maybe bring some more attention to this."

And for de Domenico and Feighery, who have long worked making commercials and feature films, it's a chance to put their craft to a higher use.

"We want to get back to a place where filmmaking is about helping society and making a difference."

"What we really need now is to talk to politicians who understand the story and are sympathetic.''

The film is tentatively titled Gagetown: Canada's Dirty Secret. They hope to have an 80- to 90-minute film ready by later this spring, the deadline for entering the Toronto Film Festival.

Feighery and de Domenico have been keeping in touch with people involved with the movie through their website: www.gagetownmovie.com.

Obesity during pregnancy linked to increased risk of babies born with abnormalities

Obesity during pregnancy linked to increased risk of babies born with abnormalities
February 11th, 2009

(PhysOrg.com) -- A Newcastle University study has shown that obese women who become pregnant have an increased risk of their baby being born with certain abnormalities, including spina bifida.

They found that women who were obese were more than twice as likely to have a baby with spina bifida, a condition which affects a very small number of pregnancies but which may result in disability.

Dr Judith Rankin from the team who carried out the study says, “Women who are thinking about trying for a baby need to check their own weight first and then think about seeking help if they are overweight. While you are pregnant it’s not the time to start a weight loss diet but it is more important to eat sensibly and healthily.”

Recent studies suggest up to a fifth of pregnant mothers are classed as obese in the UK - a figure that has doubled in the last 10 years.*

In the United States, a third of women age 15 years and older were obese in 2004.

Obese is considered as a Body Mass Index (BMI) over 30, while overweight is classed as a BMI over 25, as categorized by the World Health Organisation.

The study, out today in the academic journal JAMA, analysed and combined data from 39 previous studies to look at the risks of abnormalities in the baby for mothers who were obese or overweight.

It showed that obese women were nearly twice as likely to have a baby with neural tube defects which are caused by the incomplete development of the brain, spinal cord and/or their protective coverings. For one of those conditions, spina bifida, the risk was more than doubled.

Researchers also detected an increased risk in heart defects (cardiovascular anomaly), cleft lip and palate, a malformation of the lower bowel (anorectal atresia), increased risk of water on the brain (hydrocephaly) and problems in the growth of arms and legs (limb reduction anomaly).

For the first time, researchers found a possible link between mothers who are overweight and babies with neural tube defects, although they say more research needs to be done in this area.

“This is the first time that so many studies have been combined to build a more accurate picture and it shows a link between a mother’s weight and many of these serious conditions in the newborn baby. Given that we are seeing an increase in the number of people who are overweight or obese, then we may see an increase in the number of babies born with abnormalities”, says Dr Rankin.

Despite their findings, the researchers were keen to stress that these abnormalities are uncommon. “Spina bifida only occurs in approximately one in every two thousand births, so the risk, even among obese women, remains very low.”

The Newcastle University team will now continue the work to examine why there is a link between a mother’s weight and abnormalities in the baby.

Academic paper: Maternal Overweight and Obesity and the Risk of Congenital Anomalies. A systematic review and Meta-analysis. Katherine J. Stothard, PhD, Peter W.G Tennant, MSc, Ruth Bell, MD, Judith Rankin, PhD.

More information: JAMA. 2009;3016:636-650.

Notes:

*There are no national published figures relating to pregnancy so this figure is based on a study published in 2006 in BJOG which showed 16% of women are obese at booking in Middlesbrough.

Serious Birth Defects are Declining in North Carolina

Babies have a healthier start in life thanks to efforts led by the NC Folic Acid Council and the March of Dimes



RALEIGH, N.C. – Over the past ten years there has been a significant decline in the rate of spina bifida in North Carolina. In observance of National Folic Acid Awareness Week, January 7-13, the North Carolina Folic Acid Council (NCFAC) and the March of Dimes would like to recognize the work North Carolina has done to reduce the number of babies born with this serious birth defect.

“We’re seeing progress in the fight to eliminate neural tube defects like spina bifida thanks to folic acid fortification and an intense public health campaign to increase folic acid consumption through multivitamins,” said Amy Mullenix, MSW, MSPH, Statewide Campaign Coordinator. “Yet, there are still too many babies born with spina bifida and we want to make sure every woman of childbearing age gets the message that she should be taking a multivitamin every day, just in case.”

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Birth defects down after low-carb craze

Saturday, January 5, 2008
Birth defects down after low-carb craze
Rates have dropped 30 percent in state since peak of the diet trend in 2003

By Richard Craver
JOURNAL REPORTER

The passing of the low-carb craze and an increase in fortified, high-grain foods appears to have helped reduce the rate of birth defects in North Carolina, two nonprofit agencies said yesterday.

The N.C. Folic Acid Council and the March of Dimes reported that the rate of defects affecting the central nervous system has dropped 30 percent in the state since the low-carb fad peaked in 2003.

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