Thu. Aug 11th, 2022
Genetic origins of autism could be unlocked by Jake’s mouse
Jake Litvag visits a lab at Washington University where doctors are studying a rare form of autism linked to a mutation in a gene, using mice with the same mutation as he has.

Jake Litvag visits a lab at Washington University where doctors are studying a rare form of autism linked to a mutation in a gene, using mice with the same mutation as he has.Credit:AP

Walking out of the lab, tears welled up in Lisa Litvag’s eyes as she thought about the language within her son’s cells helping other children.

“We’re deeply proud and humbled to be part of this,” Joe Litvag said. “What do we live this life for? It’s ultimately to try to, in one way, shape or form, be of service to others.”

Jake’s gift

The Litvags realised early on that Jake wasn’t reaching childhood milestones. He couldn’t walk without assistance until he was four. He struggled to string sentences together in first grade. At first, no one could pin down why. Jake had a mix of different traits. He was hyperactive and impulsive but also social, warm and funny. It took until he was five to get a firm diagnosis of autism.

About that time, the Litvags heard that child psychiatrist Dr John Constantino, an expert on the genetic underpinnings of autism, was giving a talk at the Saint Louis Science Centre. They decided to go in the hopes of meeting him. They did, and he began seeing Jake as a patient.

About five years later, Constantino proposed genetic testing. It revealed the missing copy of the MYT1L gene believed to cause one out of every 10,000 to 50,000 autism cases. Having an extra copy can cause schizophrenia.

The finding brought the family peace. They’d heard lots of people say autism was mostly caused by external factors, such as birth trauma. “For a long time,” Lisa Litvag said, “I thought it was something that I did.”

Actually, a large multinational study suggests that up to 80 per cent of the risk for autism can be traced to inherited genes.

“One of the big things it did for us as a family is it made us realise that it’s nothing that we did wrong,” Joe Litvag said. “It’s just that people are born all the time [with genetic differences].”

The couple, whose younger son Jordan doesn’t have the condition, talked openly to Jake about his autism and tried to bolster his self-esteem when he worried about being seen as different. They sent him to a small private school that tailors its curriculum to each child’s learning abilities. And they encouraged his social tendencies, cheering him on when he and some classmates formed a band, the Snakes.

“We never wanted him to feel there was shame around his diagnosis,” Lisa Litvag said. “We continued to kind of reinforce that this is a superpower, you are special, you are awesome … and because you have autism, there are gifts you have to give other people.”

When Constantino suggested studying the little-understood MYT1L gene, the Litvags enthusiastically agreed to help. Constantino – who is on the local board of Autism Speaks, a group they’ve long been active in – asked if they’d be interested in raising money for early research.

Joe Litvag, an executive in the live music industry, and Lisa Litvag, a partner in a marketing firm, reached out to family and friends and raised the $US70,000 needed in about six months.

With half the money, researcher Kristen Kroll and her team reprogrammed cells from Jake’s blood into “induced pluripotent stem cells”, which can be prodded into becoming various cell types. With the other half, scientist Joseph Dougherty and his team followed the blueprint of Jake’s genome and induced his mutation in mice using the gene-editing tool CRISPR.

Like the people they’re meant to model, mice with the mutation tended to be more hyperactive than siblings without it, running around their cages much more. They were nonetheless generally heavier, especially the first generation of mice. They had slightly smaller brains and a little less of the white matter that speeds communication between different brain regions.

Since starting the research about three years ago, scientists have bred about 100 mice with Jake’s mutation and are now using the great-great grandchildren of the first one they engineered. They recently published about the mice in the journal Neuron.

While scientists can’t go back and see how Jake’s brain developed, Dougherty said, mice allow them to watch the mutation play out through generations.

Dougherty and his colleagues hope what they learn about how MYT1L functions ultimately leads to medicines or gene therapies that improve or even correct the problems the mutation causes.

They are sharing their findings with scientists studying other autism-causing genes or trying to figure out how various genes work together to cause the condition.

According to the Simons Foundation Autism Research Initiative, more than 100 genes have strong evidence linking them to autism and a growing list contains several hundred more genes thought to be linked to the condition.

In cases where autism is caused by a single gene, Dougherty said that gene probably does many things to brain development. A key to understanding autism overall is to find one or two things shared across different forms of autism, which could then be targets for treatment. Though not everyone with autism wants treatment, Dougherty said it could help those who do.

Since the research began, Dougherty has been writing notes to the Litvags explaining the latest discoveries. But as a lab scientist, he’s mostly removed from the people sparking the research and first met the family when they were invited by the school to visit in December.

After meeting the mice, they stopped into another lab, where Jake peered through a microscope at his blue-stained stem cells.

“That’s me! That’s cool stuff. I never saw anything like that in my life,” he said, stepping back to lean into his father, who pulled him close.

Dougherty used the visit as an opportunity to share some news, a gift of sorts that he wanted to tell the family in person.

The missing gene doesn’t seem to shorten life. The mice live two to three years, the same as their siblings.

“So, a normal life span?” Joe Litvag asked hopefully.

“Yes,” Dougherty answered. “As far as we can tell, identical. I know that’s a big relief, too.”

Joe Litvag turned to his son. “So Jake, maybe you will live to be 100.”

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