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Brain development gene emerges as strong autism candidate

by  /  2 October 2014

Distinctive faces: People with ADNP mutations tend to have high hairlines, prominent foreheads and thin upper lips.

In April 2013, Evan Eichler attended a meeting on the genetics of autism and intellectual disability in Troina, Sicily.

Eichler, professor of genome sciences at the University of Washington, had planned to present his new data on candidate genes for autism. He and his collaborators had discovered these genes by sequencing the exomes — the protein-coding regions of the genome — of 209 people with autism, and then re-sequencing a promising subset of genes in 5,189 people with autism or developmental delay.

In this list was a gene called ADNP, which Eichler’s team had found to be mutated in four people with both autism and developmental delay, as well as in one control.

In a smaller group meeting later over lunch, cognitive geneticist Frank Kooy of the University of Antwerp in Belgium showed pictures of two more children with ADNP mutations his team had identified. Eichler pulled out a picture of one of his ADNP cases.

The three children — two Belgian and one Italian  — looked remarkably alike, with high hairlines, prominent foreheads and unusually shaped eyes. “Everybody was just like, ‘Wow, this is going to be a new syndrome,’” Eichler recalls.

Kooy and Eichler decided to work together to find more people with ADNP mutations. In the year and a half since, they have found that these individuals have a syndrome that combines autism, developmental delay and distinctive facial features, including a thin upper lip and broad nasal bridge.

In two papers published this year, the researchers identified a total of 11 children with autism symptoms andADNP mutations1, 2. In July, an independent group led by Eric Morrow of Brown University in Providence, Rhode Island, reported one more case: a girl with autism who has an ADNP mutation3. Kooy says he knows of three other such children, bringing the total to 15. In all but one of the published cases, the mutations are de novo, meaning that the children’s parents do not have them. In the final case, the parents were not available for testing.

“This is a new autism gene,” says Kooy.

Shared genes:

Among the many hundreds of genes linked to autism, only a few have been clearly characterized. Typically, researchers hoping to zero in on disease subtypes identify people with similar characteristics and then sequence their DNA in hopes of uncovering mutations that contribute to the disorder.

By contrast, the ‘genotype-first’ approach begins by identifying people who have a known genetic risk factor and attempts to chart their symptoms in detail. Researchers are increasingly finding that these genetic risk factors don’t always result in autism. In many cases, they lead only to developmental delay, for example. ADNP is one of a group of genes, including CHD8 and TBR1, that appear to lead to autism in a substantial proportion of cases.

“When recurrently hit, ADNP seems to be enriched in autism as opposed to just broadly defined developmental delay,” Eichler says.

Eichler, however, eschews the idea that there is such a thing as a “‘pure’ autism gene.” He notes that only some of the children with ADNP mutations have been diagnosed with autism using the gold-standard diagnostic measures.

Among the 12 children — 7 male and 5 female — described so far, all have developmental delay, ranging from mild to severe. Apart from autism, these children also seem to have overly flexible joints and low muscle tone, are prone to infections, and have vision and gastrointestinal problems.

In 11 of the cases, the mutations are in the same section of the gene and tell the cell to stop reading the DNA. Because this section is at the end of the gene, however, the mutated gene is still transcribed into messenger RNA, and may even be translated into protein, Kooy says.

The mutation in the other case is in a more central part of the gene, and almost certainly prevents the protein from being produced, he says.

Chromatin connection:

ADNP is relatively new to the autism world, but Illana Gozes of Tel-Aviv University in Israel has been studying it for 15 years. Gozes and her colleagues identified the gene in mice in 19994 and cloned the human equivalent in 20015.

ADNP appears to be essential for brain development. In mice lacking both copies of the gene, the neural tubes don’t close during fetal development, and the animals die in utero. With just one missing copy, the mice have cognitive deficits and develop brain pathology reminiscent of Alzheimer’s disease. Gozes is trying to assess whether these mice would serve as a model for autism.

ADNP is known to interact with the BAF complex, a group of proteins that wind and unwind DNA — a process known as chromatin remodeling — to either suppress or promote gene expression. “Any changes in this system, for instance caused by a lack of ADNP, will have severe consequences for development,” Kooy says.

Other autism-linked genes, including CHD8, have been increasingly linked to chromatin remodeling. ADNP has been identified as a target of CHD8.

ADNP’s work on chromatin remodeling takes place in the nucleus of the cell, where the DNA resides. But in neurons, the protein is also present outside the nucleus, where it appears to play a separate role through eight amino acids that make up its so-called ‘NAP motif.’

Researchers have tested NAP as a treatment for schizophrenia, mild cognitive impairment and other brain disorders, with mixed success. The peptide easily crosses the blood-brain barrier and appears to be safe, leading researchers to speculate that it may also treat people with ADNP mutations.

“The NAP domain is intriguing,” says Kooy. “We can try to see, would just NAP also be able to rescue some of the autistic features in animal models?”

In the meantime, researchers are searching for people with ADNP mutations.An international group of researchers is sequencing ADNP, among a couple of hundred other genes, in around 10,000 people with developmental delay or autism and thousands of controls.

Analyzing a greater variety of mutations in the gene may help explain how the protein functions and the range of symptoms the mutations trigger.

“I still think it’s too early to understand the full scope of the phenotype,” Morrow says. “I think we’re getting a sense of it.”

References:

1. Helsmoortel C. et al. Nat. Genet. 46, 380-384 (2014) PubMed

2. Vandeweyer G. et al. Am. J. Med. Genet. C Semin. Med. Genet. 166, 315-326 (2014) PubMed

3. Pescosolido M.F. et al. J. Med. Genet. 51, 587-589 (2014) PubMed

4. Bassan M. et al. J. Neurochem. 72, 1283-1293 (1999) PubMed

5. Zamostiano R. et al. J. Biol. Chem. 276, 708-714 (2001) PubMed


13 responses to “Brain development gene emerges as strong autism candidate”

  1. autismisepigenetic says:

    how is all this genetic research going to help our kids NOW? How will this information be used in the future and by whom? to prescreen embryos? I see no direct benefit of all this gene research as far as treatment for our kids. If anything the information will be used to write our kids off as having a “preexisiting genetic condition”. Hate to sound cynical but who will this benefit…the “greater good” I guess.

    • ADNP Mom says:

      To ALL of you completely insensitive and un informed parents! My son has this Di novo ADNP mutation. You ask what will this do to “help our kids” or state nonsense like this won’t help them know…. You have no idea what you are talking about. There is something called “gene therapy” and apparently you don’t bother to see the big picture before insentivly writing your opinion, which is quite sad. As a parent of a child with this mutation, if I found this out before, I would not use this info to terminate as you think people will. But, when you have a complicated medical child, with many cognitive issues, it is very difficult to get therapy and a early diagnosis would have saved my son years of time lost while doctors where not sure what was going on. So this kind of gene discovery is good, not bad. These kids may one day be able to have some form of gene therapy to help symptoms, they can get very early intervention, and you blasting off that this is no good is just rude, insensitive and ignorant. And suggesting that people would use this as a excuse to terminate a pregnancy is nonsense as well. Although it is not my belief to terminate pregnancy, I can tell you this.LOL. This life my child has, it sucks! He can’t speak, can’t play, can’t use a bathroom, can’t take care of himself…l. He doesn’t even understand the joy that he has a twin brother because he can’t interact with him. It is a very crappy life for the child, so please try to think that ANY research that could possibly help these children is GOOD and very much needed!!!

  2. findacureforautism says:

    Its in some way to be reading articles like these one. Is supose scientist are trying to understending causes, for propuse a answer. But these clearly a human genetic pandemia and the research is like to slow looking for answer. Realy hate to be reading all the time same things, just tales and never answer!!!!

  3. ASD Mom says:

    Agree…This is insensitive. These are human beings, rather than genetic abnormalities.

  4. ReadItMoreClosely says:

    To answer “autismisepigenetic”: although this finding will not likely yield any immediate treatments for those diagnosed with autism, it does add another piece to the scientific understanding of this complex disorder. The path from basic knowledge to practical applications, whether in medicine or engineering, is often very, very long and frustrating. But to just demand an answer immediately, give up or fall back on pseudo-science will just delay the work of those actually doing the hard work of building the foundation of scientific fact on which a real treatment may eventually be built. There is no simple path.

    However, if you had been reading the article more closely, you would have noticed that the authors did in fact speculate about an actual treatment for individuals with the ADNP mutation: “Researchers have tested NAP as a treatment for schizophrenia, mild cognitive impairment and other brain disorders, with mixed success. The peptide easily crosses the blood-brain barrier and appears to be safe, leading researchers to speculate that it may also treat people with ADNP mutations.”

  5. Sam says:

    How about instead of distinguishing kids based on eye brows and foreheads….

    Start with subtyping Autism: Verbal Nonverbal, Severity of autism, Immune issues, Exczma issues, Gastrophogitis, gastrointenstinal issues…group

    • Anonymous says:

      I agree wholeheartedly agree with you about first subtyping autism in the terms you listed. The spectrum is so broad that even if researchers find a gene mutation linked to autism and then develop gene therapies or treatments, you’d have to do genetic testing on everyone before determining if the treatment is appropriate. Instead of using facial morphology as your marker, why not use behavioral and developmental phenotypes of autism, like the ones you mentioned?

  6. Medical Researcher says:

    Before we can begin to treat children with autism such as your own, we need to understand how the disease manifests. Once we understand the underlying mechanisms, we can design targeted therapies that interfere with or reverse the pathobiology of the disease. Take, for instance, fragile X. Scientists spent years trying to understand the genes and pathways leading up to the disease. After numerous studies such as the ones above, they identified parts of the pathway where we could intervene pharmacologically and stop the progression. So far, this has proven to be successful, and if it passes clinical trials, may serve as a treatment for individuals with this disorder. Indeed, people with the disease now may not benefit directly, but generations to come will. You have the see the bigger picture.

    • Sam says:

      I truely understand what you say. I have a kid non verbal autism. I see such a variation in his awareness, sleep issues. On a monthly basis, If I may describe it to you: 10 consecutive days, he goes to bed and falls sleep immediately, he is aware and plays normally. 14 other cnsecutive days, he is not aware, yells, stimms, and falls sleep at 4AM, with flares of skin lesions, non stop self urinating (which not observed during the other 10 days). If so genetic, and if the neurons that are so permanent what such a variation in behavior. I have visited MCgill autism center and I am not too sure if researchers know these facts. Why not test during awareness, and non awareness period and see what is changing/difference, neurotransmitters, immune factors that could play a role.

      The funny thing is I work in process variability in pharma manufacturing world so I dont think my observations are off the chart or just imagination. Any chance if you want to guide, please I would appreciate your views and inputs as medical researcher

      • Medical Researcher says:

        Indeed, you’ve hit upon an idea that many researchers share in the field–that autism is not a single disorder but a spectrum of disorders that is caused by many different underlying genetic alterations that act in concert with environmental influences to shape the personalities and health of individuals. It may be interesting to interrogate certain biomarkers during the periods you descibe (e.g. EEG, chem panels, etc.), but it is often difficult to make conclusions based on that data given an N of 1. If we could find many patients all who exhibit the said behavior and run a controlled study to look at the tests you proposed, that might be fruitful. But as someone who understands the concept of experimental design, it is difficult to conduct one of these studies, let alone finding the appropriate patients to enroll, the funding (private vs. academic), and possible genetic variants that contribute to the behaviors you describe. At some level, understanding the genetic basis is useful because we can attempt to tailor specific treatments to specific types of autistic patients. In some cases, however, that may fail. Ultimately, treatment will likely stem from both behavioral (addressing the environmental affects) and medical intervention. Finally, to understand human behavior is difficult. At a certain point, we lose the ability to explain people’s behavior, as strange or normal it may be. However, as neuroscientists, we try our best to understand how the brain functions, and when it is clearly not functioning right, what might be altered in the hopes of finding a way to nudge it back in the right direction.

  7. Mark says:

    The answer to everything, It falls to a caring parent to be tormented by the unknown truth of a child gifted with autism. The child may have an innate gift of understanding way beyond foolish scientific method. The dimensions of our evolved social capacities, (themselves mutations on an evolutionary conveyor belt), have enabled modern man through complexity of our modern environments, (control and regulation of population through medical technology, a combination of birth control and vaccination) to exponentially re-present that genetic legacy. The recessive enters the main stream, whereas environmental factors would in (the male sex linked) most cases secure the legacy as recessive. This science is almost as ancient as science as we know it. Genetics is fundamentally about environments, and our problems today are related to our current environments (specifically impact of birth control and virology on the gene pool). These problems are political ones. Virology and population management are driven by economics. Perhaps this is why a consensus of truth struggles to emerge. Regarding this study, I congratulate the courage which directs this work, but we all have much to learn from the senses displayed by that Autistic boy who wont speak.

  8. RA Jensen says:

    Reading the articles it is very interesting that to date almost all cases of ADNP genetic mutations are not inherited, they are caused by a de novo gene mutation. Many of the genetic syndromes with high autism risk are almost always caused by de novo gene mutations. Down Syndrome, Klinefelter Sydrome, Rett Syndrome, Willians Syndrome, 22q11 deletion syndrome among other genetic syndromes caused by de novo gene mutations. Sir Michael Rutter has asked two important questions (1) the children seldom reproduce so why haven’t they followed evolutionary law and become extinct and (2) where do these de novo gene mutations come from?

    Are no researchers interested in prevention? A number of studies have reported that environmental exposure to benzene and PCB and DDT congeners are associated with sperm mutaions in healthy males that may be risk factors for Down Syndrome, Klinefelter Syndrome, Williams Syndrome, 22q11 deletion syndrome, Prader Willis and Angelman syndrome:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1274351/

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339457/pdf/ehp.1104017.pdf

    http://www.ncbi.nlm.nih.gov/pubmed/20931230

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