Largest fragile X mutation in mice confirms model defects | Domain

massive expansion: The hundreds of nucleotides that are repeated in the FMR1 gene in mice cannot mimic its effect in humans.

Photo by Rick Dhams

The large mutation that leads to fragile X syndrome in humans does not result in the same genetic sequence in mice, which is a new phenomenon. study offers. The researchers say the work highlights the limitations of using mice for case modeling and the need to explore other model animals.

Fragile X syndrome, which causes intellectual disability and sometimes autism, stems from the expansion of a three-nucleotide repeat sequence – cytosine followed by guanine (CGG) – in the FMR1 gene. People with fragile X possess more than 200 CGG repeats, which results in gene silencing by methylation. (People with 55 to 200 recurrences, described as previous, can have different but related health conditions.)

The new study shows that in mice, FMR1 remains unmethylated and unmethylated even when the animals carry up to 341 CGG repeats.

The study investigator says the result is not unexpected Stephen Colvina graduate student in Guoping Feng . Laboratory at the Massachusetts Institute of Technology. FMR1 remains unmethylated in other mice with dilatations More than 200 CGG iterationsdouble studies I showed.

But Colvin and his team wanted to make sure that larger expansions would show the same result, paving the way away from mouse models for the fragile X. In 2019, Feng’s laboratory developed A rhesus monkey model with a mutation in SHANK3another gene linked to autism.

“I thought this would be a good model where if we can definitively demonstrate the lack of methylation in mice, it would justify transferring the fragile X research to non-human primates,” Colvin says.

TThe new mice carry an expansion from a person with fragile X syndrome rather than the typical repeat region of the mouse FMR1 gene.

In contrast to subjects with fragile X syndrome, FMR1 remained partially functional in mice, which showed elevated levels of FMR1 mRNA in multiple brain regions, including the cerebellum, hippocampus, and striatum. But their levels of FMRP, an FMR1 protein, were reduced in the cortex and cerebellum to about 25 percent of those of wild-type species.

Work appeared in August in eNeuro.

He also says that the FMR1 gene remains loose in some people with repeats of 200 or more Randy Hagerman, medical director of the Mind Institute at the University of California, Davis, who was not involved in the work. But these people don’t usually have fragile X syndrome.

The new work confirms that human and mouse genes are different enough that scientists cannot make a mouse model genetically similar to the human condition, he says. Elizabeth Berry Kravisprofessor of pediatrics and neurosciences at Rush University Medical Center in Chicago, Illinois, who was not involved in the study.

Perry-Kravis says there has been “endless” debate about whether knocking out the gene in mice has the same effects as CGG repeat expansion. Both lead to a decrease in FMRP which is similar to what we see in people with fragile X. But in people with scaling, it’s possible that there will be periods of FMRP production during embryonic development, prior to gene silencing, which could make knockout mice less valid as models for fragile X as well, Berry Kravis says.

“The paper does not answer the question,” she says, but suggests that it is not possible to make a mouse model that would settle the controversy.

It’s not clear why the gene is not methylated in mice, Hagerman says. Before moving on to non-human primates, though, which is an expensive endeavor, she says, it would be useful to see if excess CGG repeats lead to methylation in mice.

Colvin and his colleagues say they have no plans to work on a mouse model. Instead, they say they hope to begin modeling CGG expansion in monkeys as a far-reaching project.

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