Disruptions in Contactin 4 and Autism
Disruptions in the gene contactin 4—which helps the brain make connections—can stop the gene from working properly, and prevent from the brain from making networks, according to researchers in the Journal of Medical Genetics. The leader of the study, Dr. Eli Hatchwell of Stony Brook University Medical Center in New York, suggests that these disruptions—in which a child has three copies of the gene or only one copy when two are normal—-could account for up to 2.5 percent of autism cases. Hatchwell’s team did a whole genome analysis on 92 autistic patients from 81 families and compared them to 560 people without autism. Three of the patients were found to have disruptions or duplication of the DNA that disrupted contactin 4. A report in Reuters notes that the mutation is present at birth and that they were inherited from fathers without autism.
Contactin 4 is involved in the development of axons, which are the long strings that connect one neuron to another. Other disruptions of this gene are known to cause developmental delay and mental retardation.
The genetic mutation is present at birth, Hatchwell said.
“In each case a father who was reported as normal had the same thing,” he added.
“This happens in genetics all the time. Often there are cases in which someone is reported as normal. They pass it on to their child, who has severe disease.”
It could be the fathers had mild Asperger’s or some other condition that was never diagnosed when they were children. Hatchwell noted that parents today in the United States are far more likely to seek a diagnosis for autism spectrum disorder in their children than parents were in past generations.
This point about fathers having the genetic mutation, but not themselves having autism—though possibly “mild Asperger’s”—-is of interest for our family of three. I’ve noted more than a few times that my husband has ADHD (and, as through knowing Charlie, has realized that many of his closest friends are on the autism spectrum).
Reuters also notes previous research done on contactin-4 by Yale University researchers:
In 2004 researchers at Yale University found one child with developmental delays who had a deleted copy of contactin 4. In January, they and two other teams linked a gene called contactin associated protein-like 2 with some cases of autism, and a third team found a stretch of DNA on chr
The researchers of the most recent study in the Journal of Medical Genetics are now attempting to sequence the gene in large numbers of families with autism and in normal controls.
Another report from Science Daily.
Tags: asd, asperger, autism, dna, genes, Genetics, Parenting, pdd-nos
13 opinions for Disruptions in Contactin 4 and Autism
VAB
Mar 19, 2008 at 2:26 pm
Yet more evidence pointing to the fact that there is no single biological cause for the cluster of observable traits that we currently label as autism.
Beth
Mar 19, 2008 at 3:43 pm
I would love to find out if there will be follow-up studies on this and if they are looking for subjects. My husband has ADHD and I think that his father has mild AS/ADHD. There are many similarities between the three especially grandfather and grandson.
RAJ
Mar 19, 2008 at 4:18 pm
The same gene has also been found in mental retardation. Again, the failure of the autism genetic researchers to use a proper control group. If they would have used a mentally retardarded control group and reported the IQ of their ‘autism’ sample the report may have meaning, at least with genes that may contribute to mental retardation.
In every autism genetic study published this year, the so-called ‘autism’ gene has been reported in mentally retarded and/or schizophrenic people without ASD.
The Autism Genome Consortium in one of the examples published this year did not segregate the patients by IQ. A later study using a normally intelligent sample of high functioning autistic people found no cases.
These studies make no sense because they do not control for mental retardation and other conditions and therefore all lack any specificity to ‘autism’.
The wrong control groups are the general population. The correct control groups should be mentally retarded sample without autism and high functioning autism where the always confounding variable of mental retardation is eliminated.
Jill
Mar 19, 2008 at 5:00 pm
After reading the whole article, I am a little ticked off at what Hatchwell said regarding parents are more likely seek the diagnosis of autism for kids that have mild learning problems. My kids do not have a mild learning problem. I do not know if there is an epidemic or not but I do know that my kids have very little chance of living an independent life. My county MRDD went from 2,000 adults/children looking for services to over 15,000 in just ten years.
I am still not understanding why the father can have this mutation and not be affected but yet the child is. Does the child have other mutated genes?
John Gilmore
Mar 19, 2008 at 6:23 pm
Here we have yet another example of autism reporting where obvious questions are not asked: If the father has the same genetic anomaly and the father does not have autism what evidence do we have that the genetic anomaly causes autism? None. Reports like this come out at a pretty steady rate. I think it has more to do with gentic researchers trying to hang on to their grants, and medical reporters who would gladly reiterate “2+2=5″ if the person who told them that had an authoritative association.
Kristina Chew, PhD
Mar 19, 2008 at 7:01 pm
I found the observations about a father with ADHD or Asperger’s (and my husband has some Aspergerish-like traits and definitely ADHD; he would have had an IEP now) passing on the mutation to a child who then has autism of interest; the study also mentions the recent research by Michael Wigler on spontaneous vs. heritable autism.
Emily
Mar 19, 2008 at 9:53 pm
” If the father has the same genetic anomaly and the father does not have autism what evidence do we have that the genetic anomaly causes autism? None. Reports like this come out at a pretty steady rate. I think it has more to do with gentic researchers trying to hang on to their grants, and medical reporters who would gladly reiterate “2+2=5″ if the person who told them that had an authoritative association.”
It’s called “incomplete penetrance,” and I can think of, off of the top of my head, five mechanisms by which a father might not manifest symptoms but the child does not, or vice versa.
There are many examples of a parent and a child carrying the same mutations but of only the child’s manifesting symptoms. Fragile X and Huntington’s come to mind, although they are trinucleotide expansion diseases. The authors make reference to “copy number variation” in the context of the mutation, and that may be relevant, although I did not see clarification of that in my quick scan of the paper.
Anyway, the quick, off-the-top-of-my-head ways that dad could carry the mutation but not have the disorder, while child has it, are…
1. Epigenetic regulation differs between father and child. This is what makes even identical twins different in some ways, in spite of their identical genomes.
2. There are transcriptional mechanisms that influence the activity of the gene.
3. There are post-transcriptional/pretranslational mechanisms under regulation that may vary from individual to individual.
4. There are posttranslational modifications that vary from individual to individual, even with an identical gene sequence that produces an identical protein,.
5. There is a multifactorial influence that affects the level to which the pathology is manifested.
I can see why a reporter wouldn’t want to get into that.
The authors discuss this in their paper, which is open access, so anyone can read it. They provide their rationale for finding this particular mutation linked to autism. They also discuss examples of families where one manifestation of the disease appears to have a heritable mutation link, but the other manifestation seems to be de novo or arises via a completely different mechanism.
Kristina Chew, PhD
Mar 20, 2008 at 12:37 am
Thanks, Emily—I was also thinking about Wigler’s study on de novo mutations in regard to this latest study (and I think Hatchwell might have some affiliation to the Cold Spring Harbor lab where Wigler is?). I just see so many similarities between Jim and Charlie, and Charlie and me. We have different “differences,” but plenty of similarities.
RAJ
Mar 20, 2008 at 7:20 am
Ahain, contactin genetic anomalies are not specific to autism:
http://www.ncbi.nlm.nih.gov/pubmed/16571880?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The phenotype for this anomaly is mental retardation, not autism. Mentally rearded people share non autism specific isolated features that have been descried by Kanner as quai-autism, as has Romanian orphans who were subjected to early institutionalized emotional deprivation.
Emily
Mar 20, 2008 at 9:29 am
Dopamine misfiring underlies a laundry list of disorders. That doesn’t mean that somehow, dopamine misfiring isn’t related to each and every one of those disorders, and it doesn’t mean that a person with one disorder related to dopamine misfiring must also have all or any of the others.
And considering the involvement of the brain and neuronal communication in autism and in intellectual disability, I would actually expect that there would be a mechanism or mechanisms in common, especially related to short-term memory issues. But…genes are often quite long, thousands of bases long. Mutations in one part of a gene can result in a related phenotype that is entirely different from what results from a mutation in another part of the *same* gene. Thus, it doesn’t really matter in the context of this discussion that MR is linked to the same gene that the authors purport to link to autism *unless* the mutations identified in each study are identical.
Regan
Mar 20, 2008 at 9:46 am
MR is a determination from a formal instrument, and seems to have some dependency on what instrument is used and what is being measured, and when. Behaviors may be retarded relative to some stated criterion, not people.
Autism is a diagnosis based on observation, and in re: educational classification seems to be dependent on variables outside of phenotype anyway.
To me, both of those are labels and subject to definition change more easily than biology.
I have no issue with the genetic studies and am not looking for whether there is some “product based” application coming out immediately. Basic research contributes to identifying the mechanisms that relate to phenotype.
Emily, thanks for your comments.
fiona
Mar 29, 2008 at 5:36 pm
I am not a scientist, but apropos fathers of children with diagnosis of autism not appearing to ‘have’ autism themselves, is this not a cultural factor, that is mildly ‘autistic’ features in the past have been accepted as ‘eccentricity’ or the features of ‘a typical man’ and therefore not ‘pathologised’. Moreover, with foregrounding of feminist perspectives in relationships and educational issues (the desire that men are ‘empathic’) are there really more men and boys with autism around, or has our 21st century culture just highlighted what was, in its mildest form, ‘maleness’?
As for one of my sons, there is no doubt whatsoever. He is severely autistic, with limited speech and language. But beautiful, nonetheless.
Fiona
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