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 on 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.
