Autism-Linked MYT1L Mutations Cause ‘Identity Crisis’ in Budding Brain Cells | Spectrum

Mounted: Genes that are typically active in neuronal stem and progenitor cells (pink and green) have high expression in newborn mice with one (middle) or two (right) non-functional copies of MYT1L, compared to controls (to the left).

Images courtesy of Moritz Mall

Immature neurons with mutations in the autism-linked gene MYT1L fail to suppress genes that should only be active in other cell types – a deficiency that blocks neuron maturation and shifts their electrical signaling to overload, according to a study published today in Molecular psychiatry.

The anticonvulsant drug lamotrigine calms excess signaling in human and mouse neurons and suppresses hyperactivity in mice with mutations in MYT1Lthe study also shows.

Results fall far short of guaranteeing drug will help people with such mutations, says lead researcher Moritz shopping centergroup leader at the Hector Institute for Translational Brain Research at DKFZ in Heidelberg, Germany. But they’re starting to reveal how mutations in the gene lead to developmental delays and autism, he says. MYT1L is expressed throughout life, which “gives us a longer window of opportunity to intervene,” he says.

Fewer than 200 people have been diagnosed with MYT1L-related syndrome, also marked by obesity, intellectual disability and, sometimes, epilepsy. MYT1L is one of three genes necessary to induce stem cells to become neurons. And mice with a gene variant have unusually small brains and prematurely developed neurons, according to a 2021 study that detailed the first mouse model MYT1L mutations.

The new work is the first to examine how gene mutations affect human brain cells.

It shows that human and mouse neurons are similarly affected by MYT1L mutations, suggesting that mice are a good model to study the gene, says Joseph Doughertyassociate professor of genetics and psychiatry at Washington University in St. Louis, Missouri, and principal investigator of the 2021 study.

“Good to see,” he said. “That means we can test therapies in both.”

Mall and his team created mice with a non-functional copy of MYT1L. (Mice with two mutated copies died shortly after birth.) By day 15 of gestation, the developing cortices of model embryos had 37% fewer progenitor cells maturing into neurons than control embryos.

At day 18 – just before birth – expression of genes that promote cell division remained elevated in MYT1L embryos, while expression of those that trigger neurogenesis was suppressed.

At birth, the cortices of MYT1L mice were 10% thinner than those of controls.

Brain slice: At birth, mice with MYT1L variants (middle and right) have thinner cortices than controls (left).

In behavioral tests, both juvenile and adult model mice were hyperactive. Male, but not female, adult mice had altered social behavior: they did not show the usual preference for a new mouse over an unfamiliar mouse.

Adult model mice showed altered expression of genes linked to epilepsy, schizophrenia and autism, as did neurons derived from human embryonic stem cells with an MYT1L variant. Meanwhile, genes that cause cells to become muscle or heart tissue were active in neurons, suggesting an “identity crisis” that delays maturation, Mall says. “Cells cannot transition as efficiently from the progenitor stage to a differentiated neuronal state.”

The gene linked to autism ZNF462 Also Repress Nonneural Genes During Neurogenesis, Independent Team reported in January.

HHuman and mouse neurons carrying MYT1L mutations showed an increase in spontaneous electrical activity: in mouse cells with a single functional copy, spikes increased by an average of 400%.

Among the genes up-regulated in mouse and human neurons was SCN5A, which codes for a sodium channel that is typically only expressed in the heart. (The related gene SCN2Awhich codes for a neuronal sodium channel, is strongly linked to autism.) Deletion of SCN5A in cells normalized their hyperactivity, as did overexpression of MYT1L.

Treating the cells with lamotrigine, which blocks sodium channels, also quieted the excitable cells, and MYT1L mice that received injections of the drug no longer showed hyperactivity or anxious behaviors.

On track : The recorded pathways reveal that mice lacking MYT1L are hyperactive (top left), as are their neurons (top right). The drug lamotrigine calms this hyperactivity (bottom left and right).

It will be important to test lamotrigine in mouse models with different mutations in MYT1L, Dougherty says.

The sodium channel gene SCN10A, which is typically expressed in the peripheral nervous system, is active in the brain in a mouse model of Pitt-Hopkins syndrome, a 2016 study found. study. It’s possible that such misexpression of sodium channel genes is a “common theme” in rare diseases associated with autism, says Brady Mahera principal investigator at the Lieber Institute for Brain Development in Baltimore, Maryland, who led the 2016 work. Maher was not involved in the new study, but says “it’s remarkable how similar” the mice are.

Testing lamotrigine in such genetic models could allow researchers to pool enough participants for a trial, Maher says. The drug was ineffective in a little test 2001 of 28 autistic children, but it may help people with certain genetic conditions.

Because lamotrigine is already approved for use in humans, Mall says, he plans to start a clinical trial in people with MYT1L mutations as early as next year.

“Redirection is the way to go,” he says. “It could be a very low fruit.”

Cite this article: https://doi.org/10.53053/QLYF4403