Insights into the Autism Spectrum

Almost 1 percent of children born in the United States today have an autism spectrum disorder (ASD), according to the Centers for Disease Control and Prevention.

Ranging from mild developmental delays to severe social and behavioral challenges, the array of disorders that falls within the autism spectrum is broad. HHMI researchers are making progress in understanding what unifies this set of disorders at the molecular and genetic level.

HHMI investigator Evan E. Eichler at the University of Washington School of Medicine this year used high-throughput genetic sequencing to probe the genetics of autism. He collected genetic samples from 20 children with forms of ASD thought to be sporadic in origin, meaning the children had no family members with the disorder. He sequenced each child's exome—the portion of the genome that codes for proteins—as well as those of the child's parents.

Eichler and his colleagues discovered 21 mutations in the children that they had not inherited from their parents. Some of the genes were previously found to cause intellectual disability, epilepsy, and language defects.

The findings, published May 15, 2011, in Nature Genetics, support the idea that autism is caused by several genetic mutations, and different combinations of these mutations can cause different symptoms.

Research by another HHMI scientist shows that some of the genes linked to autism are also involved in other syndromes.

Robert B. Darnell, an HHMI investigator at Rockefeller University, set out to study Fragile X syndrome, the most common form of inherited intellectual disability. It was already known that Fragile X is caused by a mutation in a gene encoding the Fragile X mental retardation protein (FMRP), and that up to 90 percent of affected individuals have autistic symptoms.

Darnell discovered that when FMRP is mutated, it turns up the production of lots of other proteins by binding to molecules that translate genetic information into proteins, called mRNA, halting their translation. Some of the mRNA molecules that the FMRP attaches to are for genes that, when mutated, cause autism. The study appeared in the July 22, 2011 issue of Cell.

Also this year, HHMI investigator Huda Zoghbi of the Baylor College of Medicine pinned some of the symptoms of autism and Rett syndrome—a disease of the nervous system that falls at the far end of the autism spectrum—on a set of neurons in the brain. She showed, in a Nature paper published November 11, 2010, that a shortage of a signaling molecule called GABA can lead to autism-like symptoms.

She and her colleagues removed the protein involved in Rett syndrome from brain cells that normally produce GABA in mice. This action was enough to make the mice show symptoms such as excessive grooming.

By developing a new genetic mouse model, Gail Mandel, an HHMI investigator at Oregon Health & Science University, and colleagues showed that a type of brain cell other than neurons, called glia, also contributes to the neuropathology of Rett Syndrome.

The researchers showed that correcting a defective protein called MeCP2 in glia, even in the presence of defective neurons, dramatically extended the lifespan of mice with the disease. It also ameliorated other behavioral symptoms. This unexpected finding, published in Nature in June, 2011, opens a door for new therapies for Rett Syndrome and perhaps other disorders related to autism.

Together, these researchers are unearthing the underpinnings of a complex set of disorders. Each molecular and genetic discovery leads to the possibility of new treatments for ASDs and new hope for patients.

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Year in Review: Research Highlights

Year in Review: Research Highlights

Learn about some of the notable discoveries made by HHMI researchers in 2011.

Models of Education

15 New Plant Scientists

In 2011 HHMI partnered with the Gordon and Betty Moore Foundation to support fundamental plant science.

The New Pace of Genomics

The New Pace of Genomics

Thanks to faster, cheaper DNA sequencing, researchers are uncovering new links between genes and disease.

Illustration: Nomoco