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Mutations in frogs point to autism genes’ shared role in neurogenesis

Mutations in any of 10 autism-linked genes lead to the same overabundance of brain cells that develop into neurons, according to a new study of the mutations in frogs. The sex hormone estrogen lowers this excess, the researchers also found.

Autism is linked to hundreds of genes, but how mutations in this varied pool lead to the same traits remains unknown. The new work sought to pinpoint where the genes’ effects converge.

“Finding shared risk and resilience factors sustains our hope that the field can use the study of individual genes to find treatment targets that work more broadly,” says lead investigator Matthew State, professor of psychiatry and behavioral sciences at the University of California, San Francisco.

State and his colleagues used CRISPR to edit genes in a species of frog called Xenopus tropicalis. Although researchers typically model autism in mice, rats and even monkeys, Xenopus offers advantages from day one: Once its first fertilized cell divides into two, each daughter cell and all of its progeny stay on their respective side. As a result, a daughter cell with an edited gene on the left will grow into a tadpole with that mutation in every cell on the left half of its body — and only the left half. Researchers can also readily observe stages of brain development in the tadpoles that occur in utero in people and other animals.

The convergence the team observed suggests that all 10 of the genes studied play a role in the early development of neurons, in addition to their other functions, says study investigator Helen Willsey, a postdoctoral researcher at the University of California, San Francisco.

Understanding this role could ultimately lead to better treatments for autism, but that is still a long way off: “‘Premature’ would be too generous a word,” State says.

“What we really need right now is a molecular mechanism,” Willsey says. “In order to get therapeutics, we need to know what these genes are doing, what’s in common to them and what are some pathways we could manipulate.”

Neuron growth:

In a day, a pair of Xenopus frogs can produce thousands of embryos, which develop into tadpoles in about a week.

In each frog embryo, the researchers edited one of 10 genes strongly associated with autism: ADNP, ANK2, ARID1B, CHD2, CHD8, DYRK1A, NRXN1, POGZ, SCN2A or SYNGAP1. All 10 are expressed in the frogs’ cerebrum at stages that line up with prenatal brain development in people, the team found.

Tadpoles with any of the mutations had either unusually large or small cerebrums. And they all had a higher proportion of neural progenitor cells — those that eventually become neurons or other brain cells — to mature neurons than controls did.

“That’s what was so surprising to us,” Willsey says. “Even for genes that are thought to be primarily at the synapse, we still saw changes in brain size and neural progenitor maturation.”

In prenatal human brains, the 10 genes, plus 92 others linked to autism, all encode proteins that interact with proteins in a layer of the cortex where neural differentiation happens, an analysis of a protein-interaction database showed.

The researchers then turned down DYRK1A expression in the tadpoles’ brains using a chemical inhibitor and tested the effects of 133 cancer drugs designed to suppress cell growth; 17 drugs altered the progenitor cell ratio, including 3 that affect the body’s use of estrogen. Adding estrogen to the tadpoles’ water restored the cell imbalance. Mutations that altered the function of estrogen receptors led to the same reductions in cerebrum size as the autism genes. The work was published in Neuron in January.

The findings suggest that estrogen plays an important role in the creation of neurons, Willsey says, and that a better understanding of this role could point to treatment targets. Estrogen itself cannot be given as a treatment because of its effects on development, she says.

Estrogen may partially explain the higher rates of autism observed in boys and men, Willsey says, although at least some of the difference in prevalence may be due to underdiagnosis of the condition in girls and women. Estrogen reduces hyperactivity in zebrafish with mutations in the autism-linked gene CNTNAP2, State’s lab previously showed.

Innovative method:

The team’s method could be useful for both screening drugs and studying genes whose functions are less well known, says Sarah Elsea, professor of molecular and human genetics at Baylor College of Medicine in Houston, Texas, who was not involved in the work.

“The process they laid out is quite nice,” she says. “It’s a template to do additional work.”

It could also help researchers identify drugs to alleviate specific difficulties seen in autistic people with different underlying genetics, such as circadian rhythm disruptions that lead to sleep problems, Elsea says.

“One of the greatest possible outcomes that we have from something like this is that there might be one medication that [works in] individuals who have [autism] associated with those 10 genes,” Elsea says. “Maybe there is something that could be identified that would help make their days just a little bit better.”

The approach could also be used identify commonalities across genes related to psychiatric conditions such as schizophrenia and bipolar disorder, says Kristen Brennand, a faculty member in the psychiatry department at Yale University, who was not involved in the work.

“It’s more evidence [that] there needs to be a systematic way of manipulating” genes linked to these conditions, Brennand says.

The brain changes observed in the frogs may not relate to autism, because the 10 genes studied are known to be important for neuron and synapse development generally, says David Cutler, professor of human genetics at Emory University in Atlanta, Georgia, who was not involved in the work.

“You don’t know really what to make of it,” Cutler says. “The autism phenotype in humans is much more subtle than ‘size of brain.’ And it’s much more subtle than ‘number of neurons.’”

Still, the method could eventually point to a system that will translate to people, he says.

“Is it plausible? Yes,” Cutler says. “Are we there? No.”

The post Mutations in frogs point to autism genes’ shared role in neurogenesis appeared first on Spectrum | Autism Research News.

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THIS NOTICE DESCRIBES HOW MEDICAL INFORMATION ABOUT YOU MAY BE USED AND DISCLOSED AND HOW YOU CAN GET ACCESS TO THIS INFORMATION. PLEASE REVIEW IT CAREFULLY.

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1. Treatment: We will use and disclose your protected health information to provide, coordinate, or manage your health care and any related services. This includes the coordination or management of your health care with another provider.
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(x) Military Activity and National Security: When the appropriate conditions apply, we may use or disclose protected health information of individuals who are Armed Forces personnel (1) for activities deemed necessary by appropriate military command authorities; (2) for the purpose of a determination by the Department of Veterans Affairs of your eligibility for benefits, or (3) to foreign military authority if you are a member of that foreign military services. We may also disclose your protected health information to authorized federal officials for conducting national security and intelligence activities, including for the provision of protective services to the President or others legally authorized.

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Others Involved in Your Health Care or Payment for our Care:

Unless you object, we may disclose to a member of your family, a relative, a close friend or any other person you identify, your protected health information that directly relates to that person's involvement in your health care. If you are unable to agree or object to such a disclosure, we may disclose such information as necessary if we determine that it is in your best interest based on our professional judgment. We may use or disclose protected health information to notify or assist in notifying a family member, personal representative or any other person that is responsible for your care of your location, general condition or death. Finally, we may use or disclose your protected health information to an authorized public or private entity to assist in disaster relief efforts and to coordinate uses and disclosures to family or other individuals involved in your health care.
6. Uses and Disclosures of Protected Health Information Based upon Your Written Authorization Other uses and disclosures of your protected health information will be made only with your written authorization, unless otherwise permitted or required by law as described below. You may revoke this authorization in writing at any time. If you revoke your authorization, we will no longer use or disclose your protected health information for the reasons covered by your written authorization. Please understand that we are unable to take back any disclosures already made with your authorization.
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Following is a statement of your rights with respect to your protected health information and a brief description of how you may exercise these rights
1. You have the right to inspect and copy your protected health information
This means you may inspect and obtain a copy of protected health information about you for so long as we maintain the protected health information. You may obtain your medical record that contains medical and billing records and any other records that we use for making decisions about you. As permitted by federal or state law, we may charge you a reasonable copy fee for a copy of your records.
2. You have the right to request a restriction of your protected health information
This means you may ask us not to use or disclose any part of your protected health information for the purposes of treatment, payment or health care operations. You may also request that any part of your protected health information not be disclosed to family members or friends who may be involved in your care or for notification purposes as described in this Notice of Privacy Practices. Your request must state the specific restriction requested and to whom you want the restriction to apply.

We are not required to agree to a restriction that you may request. If we agree to the requested restriction, we may not use or disclose your protected health information in violation of that restriction unless it is needed to provide emergency treatment. With this in mind, please discuss any restriction you wish to request with your health provider.

You may request a restriction by making your request in writing to our Privacy Officer. In your request, you must tell us (1) what information you want to limit; (2) whether you want to limit our use, disclosure, or both; and (3) to whom you want the limits to apply, for example, disclosures to your spouse.
3. You have the right to request to receive confidential communications from us by alternative means or at an alternative location
We will accommodate reasonable requests. We may also condition this accommodation by asking you for information as to how payment will be handled or specification of an alternative address or other method of contact. We will not request an explanation from you as to the basis for the request. Please make this request in writing to our Privacy Officer.
4. Your may have right to amend your protected health information
This means you may request an amendment of protected health information about you in a designated record set for so long as we maintain this information. In certain cases, we may deny your request for an amendment. If we deny your request for amendment, you have the right to file a statement of disagreement with us and we may prepare a rebuttal to your statement and will provide you with a copy of any such rebuttal. Please contact our Privacy Officer if you have questions about amending your medical record.
5. You have the right to receive an accounting of certain disclosures we have made, if any, of your protected health information This right applies to disclosures for purposes other than treatment, payment or health care operations as described in this Notice of Privacy Practices. It excludes disclosures we may have made to you if you authorized us to make the disclosure, to family members or friends involved in your care, or for notification purposes, for national security or intelligence, to law enforcement (as provided in the privacy rule) or correctional facilities, as part of a limited data set disclosure. The right to receive this information is subject to certain exceptions, restrictions and limitations.
6. You have the right to obtain a paper copy of this notice from us
upon request, even if you have agreed to accept this notice electronically.
D. COMPLAINTS
You may complain to us or to the Secretary of Health and Human Services if you believe your privacy rights have been violated by us. You may file a complaint with us by notifying our Privacy Officer of your complaint. We will not retaliate against you for filing a complaint

You may contact our Privacy Officer at (704) 824-7800 for further information about the complaint process.

This notice was published and becomes effective on August l, 2011.