News Release

Thursday, July 10, 2008

Common Mechanisms May Underlie Autism's Seemingly Diverse Mutations

Study Implicates Disruption of Genes Regulated by Early Experience

Many of the seemingly disparate mutations (http://www.nimh.nih.gov/science-news/2007/tiny-spontaneous-gene-mutations-may-boost-autism-risk.shtml) recently discovered in autism (http://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-pervasive-developmental-disorders/index.shtml) may share common underlying mechanisms, say researchers supported in part by the National Institute of Mental Health (NIMH), a part of the National Institutes of Health (NIH). The mutations may disrupt specific genes that are vital to the developing brain, and which are turned on and off by experience-triggered neuronal activity.

A research team led by Christopher Walsh, M.D., Ph.D., and Eric Morrow, M.D., Ph.D., of Harvard University, found two large sections missing on chromosomes in people with autism and traced them to likely inherited mutations in such genes regulated by neuronal activity. They report their findings in the July 11, 2008 issue of Science. The study was also supported in part by the NIH’s National Center for Research Resources, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute of Child and Human Development, and the National Institute on Neurological Disorders and Stroke.

The study breaks new ground for complex disorders like autism, taking advantage of a shortcut to genetic discovery by sampling families in which parents are cousins. The researchers found genes and mutations associated with autism in 88 families from the Middle East, Turkey and Pakistan in which cousins married and had children with the disorder.

“The emerging picture of the genetics of autism is quite surprising. There appear to be many separate mutations involved, with each family having a different genetic cause,” explained NIMH Director Thomas R. Insel, M.D. “The one unifying observation from this new report is that all of the relevant mutations could disrupt the formation of vital neural connections during a critical period when experience is shaping the developing brain.”

Earlier studies had suggested that the individually rare mutations are present in at least 10 percent of sporadic cases of autism, which is the most common form.

The researchers used a technique that pinpoints from a relatively small group of families genes responsible for disorders that can be amplified by parenthood among relatives, which can increase transmission of recessive (http://www.nlm.nih.gov/medlineplus/ency/article/002052.htm#Definition) diseases. Evidence had hinted at such transmission in autism, and the large amount of genetic information obtainable from such families reduced the need for a much larger sample including many families with multiple affected members.

The ratio of females to males with autism – normally one female to four males – was less lopsided in such families in which parents share a common recent ancestor. This ratio equalized even more in a subset of these families with more than one affected member, suggesting a doubling of the rate of autism, due to recessive causes on non-sex-linked (http://www.nlm.nih.gov/medlineplus/ency/article/002051.htm) chromosomes. Also, autism-linked spontaneous deletions and duplications of genetic material were relatively uncommon in these families, suggesting recessive inherited causes.

The researchers found multiple different genetic causes of autism in different individuals with little overlap between the families in which parents shared ancestry. Yet a few large inherited autism-linked deletions, likely mutations, in a minority of families stood out. The largest turned out to be in or near genes regulated, directly or indirectly, by neuronal activity.

“Autism symptoms emerge at an age when the developing brain is refining the connections between neurons in response to a child’s experience,” explained Walsh. “Whether or not certain important genes turn on is thus dependent on experience-triggered neural activity. Disruption of this refinement process may be a common mechanism of autism-associated mutations.”

The National Institute of Mental Health (NIMH) mission is to reduce the burden of mental and behavioral disorders through research on mind, brain, and behavior. More information is available at the NIMH website, http://www.nimh.nih.gov.

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NHGRI is one of 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Extramural Research supports grants for research and for training and career development at sites nationwide. Additional information about NHGRI can be found at its Web site, www.genome.gov.

The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s Web site at http://www.nichd.nih.gov/.

NINDS (http://www.ninds.nih.gov) is the nation’s primary supporter of biomedical research on the brain and nervous system. NICHD (http://www.nichd.nih.gov/) sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information on Rett syndrome, visit http://www.ninds.nih.gov/disorders/rett/rett.htm or http://www.nichd.nih.gov/health/topics/Rett_Syndrome.cfm.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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