Three gene networks discovered in autism, may present treatment targets

autism
Quinn, an autistic boy, and the line of toys he made before falling asleep. Repeatedly stacking or lining up objects is a behavior commonly associated with autism. Credit: Wikipedia.

A large new analysis of DNA from thousands of patients has uncovered several underlying gene networks with potentially important roles in autism. These networks may offer attractive targets for developing new autism drugs or repurposing existing drugs that act on components of the networks.

Furthermore, one of the autism-related gene pathways also affects some patients with attention-deficit hyperactivity disorder (ADHD) and schizophrenia—raising the possibility that a class of drugs may treat particular subsets of all three neurological disorders.

"Neurodevelopmental disorders are extremely heterogeneous, both clinically and genetically," said study leader Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children's Hospital of Philadelphia (CHOP). "However, the common biological patterns we are finding across disease categories strongly imply that focusing on underlying molecular defects may bring us closer to devising therapies."

The study by Hakonarson and colleagues, appearing online today in Nature Communications, draws on gene data from CHOP's genome center as well as from the Autism Genome Project and the AGRE Consortium, both part of the organization Autism Speaks.

Autism spectrum disorders (ASDs), of which autism is the best known, are a large group of heritable childhood neuropsychiatric conditions characterized by impaired social interaction and communication, as well as by restricted behaviors. The authors note that recent investigations suggest that up to 400 distinct ASDs exist.

The current research is a genome-wide association study comparing more than 6,700 patients with ASDs to over 12,500 control subjects. It was one of the largest-ever studies of copy number variations (CNVs) in autism. CNVs are deletions or duplications of DNA sequences, as distinct from single-base changes in DNA.

The study team focused on CNVs within defective gene family interaction networks (GFINs)—groups of disrupted genes acting on biological pathways. In patients with autism, the team found three GFINs in which gene variants perturb how genes interact with proteins. Of special interest to the study group was the metabotropic glutamate receptor (mGluR) signaling pathway, defined by the GRM family of genes that affects the neurotransmitter glutamate, a major chemical messenger in the brain regulating functions such as memory, learning, cognition, attention and behavior.

Hakonarson's team and other investigators previously reported that 10 percent or more of ADHD patients have CNVs in genes along the glutamate receptor metabotropic (GRM) pathway, while other teams have implicated GRM gene defects in schizophrenia.

Based on these findings, Hakonarson is planning a clinical trial in selected ADHD patients of a drug that activates the GRM pathway. "If drugs affecting this pathway prove successful in this subset of patients with ADHD, we may then test these drugs in autism patients with similar gene variants," he said.

In ASDs and other complex neurodevelopmental disorders, common gene variants often have very small individual effects, while very exert stronger effects. Many of these genes with very rare defects belong to gene families that may offer druggable targets.

The three gene families found in the current study have notable functional roles. The CALM1 network includes the calmodulin family of proteins, which regulate cell signaling and neurotransmitter function. The MXD-MYC-MAX gene network is involved in cancer development, and may underlie links reported between autism and specific types of cancer. Finally, members of the GRM gene family affect nerve transmission, neuron formation, and interconnections in the brain—processes highly relevant to ASDs.

The functional activities identified in the current study are consistent with a recent multicenter study in which Hakonarson participated, published May 1 in the American Journal of Human Genetics. That study, led by scientists from Paris and Toronto, and using Autism Genome Project data, found hundreds of rare ASD-related gene variants converging on involved in neuronal signaling, synapse function and chromatin regulation (a biological process affecting gene expression). Many of the genes in these networks have been implicated in other developmental disorders besides autism.

"Even though our own study was large, it captures only about 20 percent of causing ASDs," said Hakonarson, who added that still larger studies are needed to further unravel the genetic landscape of autism. "However, strong animal data support an important role for the pathway in socially impaired behaviors modeling ASDs. Because the GRM pathway seems to be a major driver in three diseases— , ADHD and schizophrenia—there is a compelling rationale for investigating treatment strategies focused on this pathway."

More information: "The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism," Nature Communications, published online June 6, 2014. doi.org/10.1038/ncomms5074

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JVK
1 / 5 (3) Jun 07, 2014
Each time I see this picture in an article about autism and autism spectrum disorders, I wonder how much longer it will be until copy number variation is linked from ecological variation to nutrient-dependent pheromone-controlled ecological adaptations that are epigenetically effected by nutrient stress and social stress, which leads to altered cell type differentiation and to pathology via the conserved molecular mechanisms of alternative splicings in species from microbes to man.

http://medicalxpr...ent.html
anonymous_9001
5 / 5 (3) Jun 07, 2014
altered cell type differentiation and to pathology via the conserved molecular mechanisms of alternative splicings


So the presence of citrate affected alternative splicings in Lenski's E. coli which lead to the expression of citrate metabolism genes?
JVK
1 / 5 (3) Jun 07, 2014
Reconciling the deep homology of neuromodulation with the evolution of behavior
http://www.scienc...14001032

Abstract excerpt: "...behavior evolved more rapidly; even members of the same genus or species can differ in heritable behavior."

My comment: This was exemplified in white-throated sparrows by others in Atlanta whose works -- like those of Paul Katz -- I have followed for more than a decade.

See "Estrogen receptor α polymorphism in a species with alternative behavioral phenotypes" which I have repeatedly indicated answers Feierman's 1995 question to me: "What about birds?" Suddenly, he seems to think this is important to discuss -- as I suggested when I wrote: 'Insect species exemplify one starting point along an evolutionary continuum from microbes to humans that epigenetically links food odors and social odors to multisensory integration and behavior." But Feierman blocks or edits my posts to the human ethology yahoo group.
JVK
1 / 5 (3) Jun 07, 2014
Now, we see "Modulation of neural circuits: how stimulus context shapes innate behavior in Drosophila" in the same issue that the article by Katz and Lillvus appears.

This comes from Katz and Lillvus: "Article Excerpt:

"Evolution of neuromodulatory signaling through gene duplication, neofunctionalization, and loss

The molecular components of neural signaling first appeared before there were nervous systems. GPCRs, the cell surface receptors upon which peptides and monoamines commonly act, arose early in metazoan evolution [7]. They subsequently diverged through a series of gene duplication events [8–10]. Following duplication, unnecessary or redundant genes generally undergo negative selection. However, GPCRs have been preferentially retained after gene duplication events, attesting to their importance for signaling [11].

My comment: Olfactory receptors are the retained nutrient-dependent duplicated GPCRs ....

JVK
1 / 5 (3) Jun 07, 2014
... that link the epigenetic landscape to the physical landscape of DNA in the organized genomes of invertebrates and vertebrates via conserved molecular mechanisms that link species of microbes and man in any atoms to ecosystems model of how ecological variation leads to ecological adaptations.

Evolutionary theorists, like Feierman, would rather have everyone continue to believe in pseudoscientific nonsense even if that means no one ever realizes that the de novo creation of olfactory receptor genes in the link to perturbed protein folding from the sensory environment that is manifested in autism spectrum disorders and diseases associated with cell type differentiation.

See: http://dx.doi.org....1004402 "...OR2L13 has been found in two previous studies to demonstrate either altered DNA methylation in blood [9] or gene expression in brain [32] in individuals with ASD."

Feierman, is a retired psychiatrist who has ignored experimental evidence for 50 years.
JVK
1 / 5 (3) Jun 07, 2014
'Insect species exemplify one starting point along an evolutionary continuum from microbes to humans that epigenetically links food odors and social odors to multisensory integration and behavior." --excerpted from Kohl (2012) http://www.socioa...ew/17338

See also Kohl (2013) Nutrient-dependent/pheromone-controlled adaptive evolution: a model. http://www.ncbi.n...24693353

"THIS MODEL DETAILS HOW CHEMICAL ECOLOGY DRIVES ADAPTIVE EVOLUTION VIA: (1) ecological niche construction, (2) social niche construction, (3) neurogenic niche construction, and (4) socio-cognitive niche construction."

Clearly it is socio-cognitive niche construction that fails due to perturbed protein folding in ASDs and clearly the perturbed protein folding involves epigenetic effects on the de novo creation of olfactory receptor genes. Feierman, and others like him, want the focus to be on mutations, natural selection, and evolution of biodiversity.
anonymous_9001
5 / 5 (3) Jun 07, 2014
I would appreciate it if you answered my question. Quick yes or no.
JVK
1 / 5 (3) Jun 08, 2014
I would appreciate it if you -- or anyone else -- would respond to the information I have been providing about cause and effect in a series of published works during the past two decades. Alternatively, provide me with a yes or no answer to this question: "Do you think that any experimental evidence of biologically based cause and effect suggests that any organism mutates and is somehow naturally selected to evolve into another organism?"

If your answer is yes, others will continue to know you only as an anonymous fool. If your answer is no, others will wait for more answers to come from you as you explain how biodiversity arises that is not nutrient-dependent and pheromone-controlled.
JVK
1 / 5 (3) Jun 08, 2014
Israeli Middle Schools School to Include Theory of Evolution
http://www.educat...olution/

Has anyone who is familiar with the Israeli school system compared the differences between being taught to believe in the pseudoscientific nonsense of evolutionary theory (e.g., in the USA) and learning about how ecological variation results in ecological adaptations via conserved molecular mechanisms that link the epigenetic landscape to the physical landscape of DNA in the organized genomes of species from microbes to man via olfactory/pheromonal input?

For some reason, the Israelis have decided to teach evolution in the context of ecology, which suggests that Western influences might be causing a dumbing down of their students potential.

Combating Evolution to Fight Disease http://www.scienc...88.short is akin to combating it to fight ignorance.
anonymous_9001
5 / 5 (3) Jun 08, 2014
Again...

altered cell type differentiation and to pathology via the conserved molecular mechanisms of alternative splicings


So the presence of citrate affected alternative splicings in Lenski's E. coli which lead to the expression of citrate metabolism genes?
JVK
1 / 5 (3) Jun 08, 2014
I asked the anonymous fool: "Do you think that any experimental evidence of biologically based cause and effect suggests that any organism mutates and is somehow naturally selected to evolve into another organism?"

Two articles: "Accessibility of microRNA binding sites in metastable RNA secondary structures in the presence of SNPs" http://bioinforma...abstract and "RNA editing and modifications of RNAs might have favoured the evolution of the triplet genetic code from an ennuplet code" http://www.scienc...14003208 address biophysical constraints that prevent mutations and natural selection from enabling the evolution of biodiversity.

Until the anonymous fool or someone else answers my question about experimental evidence (e.g., since Lenski's evidence is not experimental evidence of evolution), we've reached an impasse.
anonymous_9001
5 / 5 (3) Jun 08, 2014
http://www.wormbo...esis.pdf

Mutations are the engine of natural selection and arise spontaneously through a myriad of mechanisms (Nei, 2007). In C. elegans, spontaneous point mutations, gene duplications, and deletions arise at rates of 2 × 10-8, 3.4 ×10-7, and 2.2 × 10-7 per gene per generation, respectively (Denver et al., 2004;Lipinski et al., 2011). These alterations to the genome result from replication and repair errors, endogenous oxidative damage, and exogenous
environmental insults (Denver et al., 2009).


http://www.plosge....0020176

Genome sequence evolution results from the interplay between mutagenesis and natural selection.


JVK
1 / 5 (3) Jun 08, 2014
Stop touting the pseudoscientific nonsense that you were taught to believe in. Others are being taught to compare the ridiculous theory with what is known about ecology.

http://www.educat...olution/

"System-wide Rewiring Underlies Behavioral Differences in Predatory and Bacterial-Feeding Nematodes" with different morphological and behavioral traits, and the traits are nutrient-dependent and pheromone-controlled in species from microbes to man. http://linkinghub...12015000

This is only one of the model organisms I used as an example of cause and effect in my published work. Nutrient-dependent/pheromone-controlled adaptive evolution: a model.
http://www.ncbi.n...24693353
anonymous_9001
5 / 5 (3) Jun 08, 2014
The first link I posted has 8 PAGES worth of citations filled with experimental evidence of how mutations occur and what effects they have. That's far from pseudoscientific nonsense. If you can't point out what, precisely, is wrong with it and how it's flawed research, don't bother criticizing it.
JVK
1 / 5 (3) Jun 08, 2014
What's wrong with pseudoscientific nonsense is that it cannot be compared to biological facts that I have detailed in the context of cause and effect. The facts are clear.

"System-wide Rewiring Underlies Behavioral Differences in Predatory and Bacterial-Feeding Nematodes" with different morphological and behavioral traits, and the traits are nutrient-dependent and pheromone-controlled in species from microbes to man.

You prefer theory. Accept the fact that you will never understand the facts about cell type differentiation and that you will always be an anonymous fool. You will be among those who continue to retard scientific progress that is required to understand ASDs and other developmental disorders.
JVK
1 / 5 (3) Jun 08, 2014
Examples of pseudoscientific nonsense:

Roles of Mutation and Selection in Speciation: From Hugo de Vries to the Modern Genomic Era http://gbe.oxford...abstract

"...we will not consider geographical and ecological factors..."

My comment: Evolutionary theorists are allowed to not consider any factors that don't fit their ridiculous theories.

Mutation-Driven Evolution http://www.amazon...99661731
"...genomic conservation and constraint-breaking mutation is the ultimate source of all biological innovations and the enormous amount of biodiversity in this world."

After ignoring factors that don't fit, theories can be invented that defy what is known about physics, chemistry, and conserved molecular mechanisms that link ecological factors to ecological adaptations without any consideration whatsoever for mutations, natural selection, and the evolution of biodiversity (i.e., pseudoscientific nonsense).
anonymous_9001
5 / 5 (3) Jun 09, 2014
You prefer theory.


I repeat: 8 PAGES worth of citations filled with experimental evidence of how mutations occur and what effects they have

That is far from "theory".

"...we will not consider geographical and ecological factors..."

My comment: Evolutionary theorists are allowed to not consider any factors that don't fit their ridiculous theories.


Trimming extraneous factors does not instantly negate what they're focused on investigating. If you could make a logical case as to WHY not taking those into consideration falsifies their research, you might be more convincing.

For the hundredth time, "constraint-breaking" doesn't mean what you think it means. Are you under the impression that mutations break the laws of physics or something?
Captain Stumpy
5 / 5 (2) Jun 09, 2014
What's wrong with pseudoscientific nonsense is that it cannot be compared to biological facts that I have detailed in the context of cause and effect
@jk
and whats wrong with your comments is that you cannot comprehend what you are talking about because you are so focused on trying to prove mutations don't exist that YOU PROVED that they DO exist! with this: Nutrient-dependent/pheromone-controlled adaptive evolution: a model. http://www.ncbi.n...24693353
so maybe the reason you've not been getting answers for the "last two decades" is because you're so confused you cannot comprehend what is really being said... proof of that is here
Lenski's evidence is not experimental evidence of evolution
just like YOUR MODEL supports evidence of evolution through mutation, so does Lenski's
YOUR MODEL CREATES MUTATIONS, and therefore is more supporting evidence for evolution, which is also supported by Lenski et al.

JVK
1 / 5 (2) Jun 09, 2014
Anyone interested in why autism spectrum disorder research has not progressed can attribute the problem to anonymous fools and idiot minions of biology teachers like those who comment here and prevent intelligent discussion.
Captain Stumpy
5 / 5 (1) Jun 11, 2014
why autism spectrum disorder research has not progressed can attribute the problem to anonymous fools and idiot minions
@jk
you mean people like YOU who continually post contradictory statements, who cannot comprehend their own field, or who make stuff up as they go along and hope no one notices????
yep! you can blame idiots like that! idiots that say in one breath
since Lenski's evidence is not experimental evidence of evolution
or
Examples of pseudoscientific nonsense:
Roles of Mutation and Selection in Speciation
while forgetting that their OWN MODEL is proof of MUTATIONS!
I guess those idiots deserve the reputation of pseudoscience crackpot! how does that feel, jk? How does Mensa feel about you abusing their name with your idiocy?

given that you cannot comprehend SCIENCE
then you promote PSEUDOSCIENCE
JVK
1 / 5 (2) Jun 11, 2014
Programmed DNA elimination in multicellular organisms http://www.scienc...14000197 is the most recent published work to again remove mutations from any consideration whatsoever in the context of typical brain development, which is nutrient-dependent and pheromone-controlled.

That fact would make it easier to determine what goes wrong in cases of atypical brain development associated with ASDs if only biology teachers and their idiot minions would quit touting their pseudoscientific nonsense about mutations, natural selection, and the evolution of biodiversity.

Ecological variation is the determinant of ecological adaptations manifested (or not) in the morphological and behavioral phenotypes of species from microbes to man. Mutations perturb protein folding, which is how they perturb brain development in people with assumed names like Captain Stumpy who appears to be a brain-damaged Air Force Staff Sergeant.
Captain Stumpy
5 / 5 (1) Jun 12, 2014
Mutations perturb protein folding, which is how they perturb brain development
@jk
so now we know what happened to you
GIVEN that mutations "perturb" protein folding
and GIVEN that your model creates mutations, are you now saying that your model cannot perform as you previously specified (ad nauseum)????
because YOUR model creates mutations, so... any comment like
quit touting their pseudoscientific nonsense about mutations
SPECIFICALLY must then also refer to your model!
I understand my education makes you feel emasculated, which is why you also attack other people who actually know what they are talking about. Your feelings of inadequacy start pricking at you and you want to lash out at anyone with an education which you could not get.

It's ok... I see this a lot with the pseudoscience crowd... especially the ones who actually believe in the nonsense they are regurgitating all over the net. Why would you be any different?
JVK
1 / 5 (1) Jun 12, 2014
Why would you be any different?


Because I am a medical laboratory scientist, and have published books, a award-winning book chapter, and several peer-reviewed journal articles and more than 1000 blog posts during the past four years on the topic of cell type differentiation in species from microbes to man.

See also: Horizontal genome transfer as an asexual path to the formation of new species http://dx.doi.org...ure13291

It suggests cell type differentiation does not arise via mutations that theorists imply create functional new proteins. Thus, cell type differentiation appears to be nutrient-dependent and pheromone-controlled via epigenetic effects on chromosomal rearrangements that PZ Myers and his idiot minions ruled out despite the series of citations I provided in the context of extended discussion.

http://freethough...s-place/
Captain Stumpy
not rated yet Jun 12, 2014
I am a medical laboratory scientist
@jk
glorified lab tech
and have published books
so do I, although most people don't read technical manuals for fun nor do they read the CFR's for kicks
several peer-reviewed journal articles
all which support evolution as well as mutation
more than 1000 blog posts during the past four years
where you CONFUSE your own work as well as argue against it with your desire to promote a religious philosophy
cell type differentiation does not arise via mutations
so your model is NOT legitimate now? by putting this in the same paragraph as
cell type differentiation appears to be nutrient-dependent and pheromone-controlled via epigenetic effects on chromosomal rearrangements
you are simply PROVING that you are an idiot, and that you cannot comprehend that your OWN MODEL CREATES MUTATIONS

THIS is why you are considered a pseudoscience crackpot. you can't get it straight.
likely due to a lack of education
JVK
1 / 5 (1) Jun 12, 2014
Mechanism explains complex brain wiring

http://www.scienc...3244.htm

An idiot minion wrote: "Even less "generalizable" are the molecular dynamics involved in early embryogenesis."

Excerpt from: http://www.ncbi.n.../9047261
"Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species, Drosophila melanogaster and Caenorhabditis elegans..."

If the molecular mechanisms of cell type differentiation were not conserved in every species from microbes to man, the only way for ecological variation to cause ecological adaptations would be via mutations and natural selection that somehow enabled the creation of new functional proteins associated with increasing organismal complexity and the evolution of biodiversity manifested in morphological and behavioral phenotypes.

Mutations do not enable ecological adaptations!
JVK
1 / 5 (1) Jun 12, 2014
ASDs exemplify the failure of ecological adaptations.

http://www.scienc...3244.htm

"... indicate for the first time the significance of why different sets of the same protein variations can occur in one neuron and it could explain mechanistically how this contributes to the complex wiring in our brain. Although this research was done with fruit flies, it also provides new insights that help explain the wiring and complex interactions of the human brain and shine a new light on neurological development disorders such as autism. Thorough knowledge of nerve cell creation and their neural interactions is considered essential knowledge for the future possibility of using stem cell therapy as standard treatment for certain nervous system disorders."

The idiot minions of biology teachers like PZ Myers exemplify the fact that ignorance of biological facts is not a beneficial ecological adaptation in most modern human populations.
Captain Stumpy
not rated yet Jun 12, 2014
Mutations do not enable ecological adaptations!
@jk
so what you are saying then is that your model for diversity is completely out the window, because you say
Mutations do not enable ecological adaptations!
but at the same time promote mutations with this
Nutrient-dependent/pheromone-controlled adaptive evolution: a model
no wonder you are considered a pseudoscience crackpot. remember when we talked about mutations?I asked
DOES your model make any changes to the nucleotide sequence of the genome of an organism, virus, or extrachromosomal genetic element?
This is a yes or no answer
to which you answered
YES!
--Thanks for asking
so, drawing from your own words AGAIN...
IF mutations are BAD AND you say yourself that your model causes mutations
YES!
--Thanks for asking
THEN one can only conclude, per your own words and conclusions, that YOU are an IDIOT! and that you don't understand your own model let alone your field!

YOUR logic& YOUR words, jk
JVK
1 / 5 (1) Jun 12, 2014
11 Young Neuroscientists Share Their Cutting-Edge Research
http://www.wbur.o...n-videos

My comment:
Nutrient-dependent/pheromone-controlled adaptive evolution: a model
http://www.socioa...ew/20553

and

Human pheromones and food odors: epigenetic influences on the socioaffective nature of evolved behaviors
http://www.ncbi.n...3960071/

extend our 1996 model of cell type differentiation across species from microbes to man using the conserved molecular mechanisms of amino acid substitutions that link ecological variation and the metabolism of nutrients to species-specific pheromones that control the physiology of reproduction.