More info on Gene Linked to Autism

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Gene Linked To Autism In Families With More Than One Affected Child

Autism spectrum disorders

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. , 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 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. "

[Guest guest]

OK... so could the solution be as simple as replacing the missing (or

dysfunctional) protein for some kids?

On the website...

http://www.genome.gov/Pages/EducationKit/booklet6.html

under the heading " Gene-based therapy " it says...

" Great medical benefit likely will derive from drug design that's guided by

an understanding of how genes work and what exactly happens at the molecular

level to cause disease. For example, the causes of adult-onset diabetes and

the resulting complications remain difficult to decipher and, so, to treat.

But researchers are optimistic that a more precise understanding of the

underlying causes will lead to better therapies. In many cases, instead of

trying to replace a gene, it will be more effective and simpler to replace

the protein the gene would give rise to. Alternatively, it may be possible

to administer a small molecule that interacts with the protein as many drugs

do and changes its behavior. "

Caroline

> From: Doris and Steve <sjsmith@...>

> Reply-< >

> Date: Wed, 18 Oct 2006 19:51:45 -0400

> Subject: More info on Gene Linked to Autism

>

> 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.