Gene Linked to Autism in Families with More
Than One Affected Child
A version of a gene has been linked to autism in families that
have more than one child with the disorder. Inheriting two copies
of this version more than doubled a child’s risk of developing
an autism spectrum disorder, scientists supported by the National
Institutes of Health’s (NIH) National Institute of Mental Health
(NIMH) National Institute of Child Health and Human Development
(NICHD) have discovered. In a large sample totaling 1,231 cases,
they traced the connection to a tiny variation in the part of the
gene that turns it on and off. People with autism spectrum disorders
were more likely than others to have inherited this version, which
cuts gene expression by half, likely impairing development of parts
of the brain implicated in the disorder, report Drs. Daniel Campbell,
Pat Levitt, Vanderbilt Kennedy Center at Vanderbilt University,
and colleagues, online during the week of the October 16, 2006
in the Proceedings of the National Academy of Sciences.
“This common gene variant likely predisposes for autism in combination
with other genes and environmental factors,” said Levitt. “It exerts
the strongest effect detected thus far among autism candidate genes.”
Autism is one of the most heritable mental disorders. If one identical
twin has it, so will the other in nearly 9 out of 10 cases. If
one sibling has the disorder, the other siblings run a 35-fold
greater-than-normal risk of having it. Still, scientists have so
far had only mixed success in identifying the genes involved.
While most previous studies had focused on genes expressed in
the brain, Levitt’s team saw a clue in the fact that some people
with autism also have gastrointestinal, immunological or neurological
symptoms in addition to behavioral impairments. They focused on
a gene that affects such peripheral functions as well as the development
of the cortex and cerebellum, brain areas disturbed in autism.
Moreover, it is located in a suspect area of chromosome 7 that
has been previously linked to autism spectrum disorders.
This MET receptor tyrosine kinase gene codes for a protein that
relays signals that turn on a cell’s internal machinery and is
known to play a key role in both normal and abnormal development,
such as cancer metastases (hence its name). Levitt’s group and
others had earlier found that impairing the receptor’s signaling
interferes with neuron migration and disrupts neuronal growth in
the cortex and similarly shrinks the cerebellum — abnormalities
also seen in autism.
To explore this possible connection, the researchers looked for
associations between the brain disorder and nine markers in the
MET gene, sites where letters in the genetic code vary among individuals.
They tested two samples: the first, 204 families, including 26
with more than one child with autism spectrum disorders, the second,
539 families, including 452 with such multiple affected children.
One marker, the C version, emerged as over-transmitted at “highly
significant” levels in people with autism spectrum disorders in
both samples. Moreover, this association held only for families
with more than one affected child and was strongest in a sub-sample
of those with more narrowly-defined autism. The C version was significantly
less prevalent in a group of 189 unrelated controls than in the
individuals with autism or their parents.
In cell culture tests, the researchers determined that the C version
is weak at making the MET receptor protein, resulting in a two-fold
reduction in gene expression compared to the other common G version
of the gene, with presumably adverse consequences on brain development.
Inheriting two copies of the C version boosted risk for autism
spectrum disorders 2.26-fold, while inheriting one copy of C and
one of G increased risk 1.54-fold.
“Since autism likely involves complex interactions between many
different genes and other factors, common genetic predisposing
factors are likely more influential in families with multiple affected
members,” explained Levitt. “Some cases in families with only one
affected member more likely stem from rarer genetic glitches or
other sporatic events. Hence, finding the link with the MET gene
variant only in the former ‘multiplex’ families strengthens its
candidacy.”
The researchers propose that in some individuals with autism spectrum
disorders who also develop digestive and immune system or non-specific
neurological problems, the MET gene variant might play a role in
impairing both brain and peripheral organ development.
“We know that autism is the most heritable of neuropsychiatric
disorders, but, thus far, we have not identified genes that consistently
are associated with this developmental brain disease,” said NIMH
Director Thomas Insel, M.D. “This new finding is an important clue,
which if replicated in an independent sample, will take us closer
to understanding the genetic basis of autism.”
Also participating in the study were: Daniel Campbell, James Sutcliffe,
Philip Ebert, Vanderbilt University; Roberto Militerni, Carmela
Bravaccio, University of Naples (Italy); Simona Trillo, Associazione
Anni Verdi; Maurizio Elia, Oasi Maria SS; Cindy Schneider, Center
for Autism Research and Education; Raun Melmed, Southwest Autism
Research and Resource Center; Roberto Sacco, Antonio Persico, University
Campus Bio-Medico and Fondazione Santa Lucia.
The research was also supported by The Autism Genetic Resource
Exchange (AGRE), Cure Autism Now, the Marino Autism Research Institute,
Telethon-Italy, National Alliance for Autism Research, Foundation
Jerome Lejeune, and NARSAD. For more information about autism spectrum
disorders see: http://www.nimh.nih.gov/healthinformation/autismmenu.cfm.
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.
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 Web site at http://www.nichd.nih.gov/.
The National Institutes of Health (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. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov. |