Williams syndrome mouse hones in on genetic culprits

A mouse model of Williams syndrome pinpoints a genetic region associated with the social behavior seen in the disorder, and may also yield insights into autism, says researcher Uta Francke, professor emeritus of genetics at Stanford University.

At an interdisciplinary symposium on Williams syndrome held at the Allen Institute for Brain Science in Seattle on Thursday, Francke discussed the novel method she used to develop the mouse, which replicates the entire deletion of the chromosomal region associated with the disorder.

Williams syndrome is caused by the deletion of a large region of chromosome 7 encompassing 25 different genes. About 20,000 to 30,000 people in the U.S. have the disorder, according to Terry Monkaba, executive director of the Williams Syndrome Association, which organized the symposium.

People with Williams syndrome are extremely sociable, talkative and unafraid of strangers. Superficially, the condition would seem to be the opposite of autism, which is characterized by language delays and social impairment. But people with either condition have some similar challenges, such as anxiety, cognitive impairments and difficulty maintaining close relationships.

Earlier this year, scientists uncovered evidence of a genetic link between the two conditions. Some people who have a duplication — that is, an extra copy of the genes — in the Williams syndrome region have autism-like features.

Rather than knocking out all of the genes, Francke created two strains of mice, each lacking half of the region. The researchers describe these deletions as proximal and distal. When the two strains are cross-bred, some of the offspring inherit both deletions¹. “This models a complete Williams syndrome deletion,” Francke says. “It will give us more information than doing a single deletion, but it’s a lot more work.”

By comparing the mice with the different deletions to each other, and to genetically normal mice, Francke began to tease out which parts of the region are linked to different abnormalities, narrowing down the genes that might be responsible.

Zooming in:

For social features of the disorder, she says, “the proximal deletion is where the action is.” Mice with the proximal deletion and the full deletion both show the increased social behavior and anxiety reminiscent of Williams syndrome. Mice with the distal deletion have the cognitive deficits associated with the disorder.

At the symposium, Jacqueline Crawley of the National Institute of Mental Health, who has created mouse models of a variety of disorders, including autism, said that Francke’s research team “did a beautiful job on the behavioral characterization of these mice.”

Genes in the proximal deletion include LIMK1, CLIP2, GTF2I, and GTF2IRD1. It’s not yet clear which of these is responsible for the social abnormalities. “They could be the [same] genes that contribute to autistic-like features in the duplication patients,” Francke says.

However, whether duplications of the region lead to autism is still under debate.

Children with duplications of the region often have severe separation anxiety and are very slow to open up in new social situations — but they’re not uninterested in social interaction altogether, notes Lucy Osborne, associate professor of medicine and molecular genetics at the University of Toronto.

“There are obviously features in both Williams syndrome and kids with the duplications that interact with autism,” Osborne says. “But I don’t think that looking at the duplications will reveal genes for autism.”

Still, Francke argues that the Williams syndrome mouse could be useful in studies of autism. For example, if the mouse were bred with one that has features of autism, she asks, would the offspring exhibit normal social behavior — that is, would the abnormalities cancel each other out?

Francke is leaving such questions for other researchers to answer: as an emeritus professor, she no longer maintains a laboratory. For now, one of her collaborators, associate professor of bioengineering Karl Deisseroth maintains a colony of the mice in his laboratory at Stanford University. “I’m interested in making sure the mice get used by people,” Francke says.

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