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Autism-related conditions converge on same loss of DNA tags

Mutations in the gene DNMT3A disrupt how other genes are turned on and off, and can lead to a range of neurodevelopmental conditions, a study in mice has found.

The results hint at how mutations in DNMT3A, seen in people with autism and a related condition called Tatton-Brown Rahman syndrome, interfere with brain function, says lead investigator Harrison Gabel, assistant professor of neuroscience at Washington University in St. Louis, Missouri.

DNMT3A codes for a protein that deposits a chemical tag called a methyl group onto the DNA base cytosine. The protein targets only those cytosine molecules that are followed by another base, called adenine, in a DNA sequence. This type of chemical modification, called ‘CA methylation,’ occurs primarily after birth in neurons and accumulates during the first 18 months of life, when neurons are forming connections with other cells, Gabel says.

The protein missing in Rett syndrome — a rare condition characterized by language deficits and repetitive behavior — typically binds to CA methylation sites. So Gabel and his team hypothesized that disrupting the activity of DNMT3A would affect the same cellular mechanisms as those involved in Rett syndrome.

Mice with mutations in DNMT3A show changes in gene expression that mirror those observed in mouse models of Rett syndrome, they found.

“Looking for shared underlying pathology is really important, so that we can start to think about therapeutic approaches that can ameliorate the effects of more than one neurodevelopmental condition,” Gabel says.

Methylation changes:

The researchers assessed the effects of nine DNMT3A mutations on DNA methylation in cultured neurons. All nine blocked methylation at CA sites. Mutations associated with intellectual disability had stronger effects than those associated with autism, they found.

The team then deleted one copy of DNMT3A from mice and found that the rodents were heavier and had longer bones, on average, than control mice. These physical features are similar to the overgrowth seen in people with Tatton-Brown Rahman syndrome.

The mice lacking DNMT3A also showed social deficits and other behaviors that resemble core autism traits: The mice spent less time than controls inspecting a new mouse or a new object, and as pups they squeaked less for their mothers than control mice did.

The mice’s neurons have nearly half the usual amount of CA methylation, the researchers found, especially at enhancers, portions of the genome that can regulate gene expression. As a result, several genes showed altered expression.

Many of these genes are also altered in mouse models of Rett syndrome, which suggests that some traits in people with DNMT3A mutations arise from cellular changes like those in people with Rett syndrome, Gabel says. The study was published in November in Cell Reports.

Convergent pathways:

The findings also suggest that CA methylation at enhancers is critical for brain development, and that mutations in DNMT3A contribute to neurodevelopmental conditions, says Magdalena Janecka, assistant professor of psychiatry at the Icahn School of Medicine at Mount Sinai in New York City, who was not involved in the work.

“But this is a study in mice, so it’s a very big leap to say that those mutations are definitely causative of the disease in humans,” Janecka says.

The convergence between mice with one working copy of DNMT3A and mouse models of Rett syndrome is “surprising,” says Annie Vogel Ciernia, assistant professor of biochemistry and molecular biology at the University of British Columbia in Vancouver, Canada, who was not involved in the study. Ciernia notes that mice with one working copy of DNMT3A don’t seem to have the severe motor deficits observed in Rett syndrome mice, perhaps because different types of neurons are affected. But, she adds, “it’s interesting how you can have overlap in the molecular mechanism that leads to very different phenotypic outputs.”

The challenge for researchers is to understand why different mutations can lead to similar features, says Zhaolan Zhou, professor of genetics at the University of Pennsylvania in Philadelphia, who was not involved with the study. Therapeutic applications are years away, Zhou adds, but finding shared features across different conditions could help scientists identify core mechanisms to target.

Next, Gabel and his team plan to assess whether other genes associated with autism affect the methylation at CA sites. They also intend to investigate how CA methylation regulates gene expression in the brain.

The post Autism-related conditions converge on same loss of DNA tags 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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Your protected health information may also be used and disclosed to pay your health care bills and to support the operation of our practice.
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We may use or disclose your protected health information, as necessary, to provide you with information about treatment alternatives or other health--related benefits and services that may be of interest to you. You may contact our Privacy Officer to request that these materials not be sent to you.
4. Other Permitted and Required Uses and Disclosures That May Be Made Without Your Authorization or Opportunity to Agree and Object:
We may use or disclose your protected health information in the following situations without your authorization or providing you the opportunity to agree or object. These situations include:
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(iv) Health Oversight: We may disclose protected health information to a health oversight agency for activities authorized by law, such as audits, investigations, and inspections. Oversight agencies seeking this information include government agencies t-rat oversee the health care system, government benefit programs, other government regulatory programs and civil rights laws.

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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.