Common Mechanisms May Underlie Autism's Seemingly
Study Implicates Disruption of Genes Regulated by Early
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.”
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Reference: Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS,
Mukaddes NM, Balkhy S, Gascon G, Hashmi A, Al-Saad S, Ware J, Joseph
B, Parlow JN, Barry B, Yao H, Markianos K, Ferland RJ, Greenberg
ME, Walsh CA. Identifying autism loci and genes by tracing recent
shared ancestry. Science. 2008 July 11;320 (5886)