Public release date: 25-Apr-2012 [ | E-mail | Share ]

Contact: Peter Tarr tarr@cshl.edu 516-367-8455 Cold Spring Harbor Laboratory

Cold Spring Harbor, NY A team led by scientists at Cold Spring Harbor Laboratory (CSHL) publishes research today indicating a striking association between genes found disrupted in children with autism and genes that are targets of FMRP, the protein generated by the gene FMR1, whose dysfunction causes Fragile-X syndrome. The new study appears online April 25 in the journal Neuron.

Fragile-X syndrome is the most common cause of inherited intellectual disability. It is also counted among the autism spectrum disorders (ASDs) owing to the co-occurrence of autism-like symptoms in patients. A usually devastating disorder, Fragile X occurs when the FRM1 gene fails to direct nerve cells to manufacture FMRP, the FMR1-encoded protein, which plays a vital role in neural development and synaptic plasticity.

"A surprising proportion -- up to 20% -- of the candidate genes we see in our sample drawn from 343 autism families appear to be regulated by FMRP," says CSHL Research Investigator Dr. Michael Ronemus, co-first author of the new study. "Because of research connecting FMRP to the phenomenon of neuroplasticity, our work indicates a possible convergence of mechanisms causing autism," adds CSHL Professor Michael Wigler, the senior author of the study. Neuroplasticity is the process by which our brains become sensitized and desensitized to repetitive inputs.

Besides team leader Wigler, a geneticist, others who worked on the study included CSHL sequencing authority Dr. W. Richard McCombie, a sequencing team at Washington University, St. Louis, and Drs. Michael Schatz, Ivan Iossifov and Dan Levy of CSHL, all computational biologists.

Families studied by the team were part of the Simons Simplex Collection. This collection is comprised of "simplex" autism families: those with at least two children, only one of whom has autism spectrum disorder or ASD. In such cases, disease causation has been previously linked to de novo, or spontaneously occurring, gene mutations.

The new research reached its conclusions based on full exome sequencing of each family member's genome. The exome is the portion of the genome less than 2% of the total -- in which DNA encodes proteins. By studying simplex families, researchers seek to discover, among other things, the fraction of autism caused by gene mutations that are not inherited.

This study focused on small-scale de novo mutations changes in DNA as small as a single DNA "letter" relative to the normal sequence, and small insertions or deletions as large as 10 or 15 letters. In the majority of children with small de novo mutations those mutations traced to the father's germ cells (sperm), in an age-dependent manner. Thus, the children of older parents were more likely to have the sorts of mutations that can cause autism.

There are many types of gene mutations, some more likely to result in biological dysfunction than others. One of the most important findings of this study concerned the type of small-scale de novo mutations most likely to play a causative role in autism. "We found that those small-scale de novo changes that disrupt genes in other words, those that disrupt the production of a normal length protein -- are twice as frequent in affected vs. unaffected children," says CSHL Assistant Professor Ivan Iossifov, a quantitative biologist who is the study's other co-first author. (In technical terms, these "disrupting" mutations include frame-shift, splice-site, and nonsense mutations, but not missense mutations.)

Continued here:
A striking link is found between the Fragile-X gene and mutations that cause autism

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