Insufficient single gene to account for dup15q, Angelman traits | Spectrum

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Active cell: Neurons with genetic mutations in the 15q11-13 chromosomal region have increased excitability and atypical synaptic function.

Multiple genes shape traits of the autism-related conditions dup15q syndrome and Angelman syndrome, according to two new unpublished studies. The work was presented Tuesday at Neuroscience 2022 in San Diego, California.

Angelman syndrome is caused by deletions or mutations in the maternal copy of chromosomal region 15q11-13, whereas dup15q syndrome results from its duplications. Although the traits differ for the two conditions — dup15q more frequently results in autism, for example — both syndromes are linked to an increased likelihood of seizures and developmental delay.

Researchers have long suspected that a single gene in the region, UBE3A, drives Angelman syndrome, and it has also been considered an important target for dup15q syndrome. Over- or under-expression of the maternal, but not the paternal, region 15q11-13 leads to either condition, leading researchers to think that UBE3A, which is silenced on the paternal copy through imprinting, is a fault.

Persons with Angelman syndrome who lack expression of UBE3A and other genes within the 15q11-13 region have more severe traits than those who lack only UBE3A. And animal models that overexpress UBE3A do not fully capture the dup15q syndrome phenotype, suggesting that other genes also shape traits associated with that condition.

But which traits result from atypical UBE3A expression, and which other genes might be involved, isn’t clear, says Marwa Elamin, a postdoctoral fellow in Eric Levine’s lab at the University of Connecticut School of Medicine at Farmington, who presented one of the posters .

The new work confirms that changes in UBE3A expression contribute to many, but not all, of the atypical traits observed in neurons carrying dup15q and Angelman syndrome mutations.

The findings have important implications for the development of treatments, says Ben Philpot, a professor of cell biology and physiology at the University of North Carolina at Chapel Hill who was not involved in the studies. “Targeting some of the other genes could also provide therapeutic benefits.”

NoEuros grown from stem cells from people with dup15q syndrome fire more spontaneous action potentials than control neurons that have the same genetic background but no extra chromosomal regions, the researchers previously reported. That kind of extra activity could lead to the seizures seen in people with the condition, the team speculates.

Dup15q neurons also have decreased inhibitory postsynaptic currents and a more permeable cell membrane, the team found in the study presented by Elamin, also available as an unpublished preprint. Downregulation of UBE3A expression using an antisense oligonucleotide (ASO), a short strand of RNA that can modify protein expression, normalizes cell spontaneous activity and intrinsic excitability, but does not alter cell membrane permeability .

The most common form of dup15q syndrome results from an “isodencentric duplication,” resulting in two extra copies of the maternal chromosomal region 15q11-13. Since paternal UBE3A is silent, this results in three functional copies of the gene compared to the typical one.

To replicate the same excess of UBE3A without overexpressing other genes within the 15q11-13 region, Elamin and his colleagues used neurons derived from a person who has two copies of UBE3A on the paternal chromosome and used an ASO to silence those copies. Overexpression of UBE3A replicated the intrinsic hyperexcitability observed in dup15q cells but not the impaired synaptic transmission or increased membrane permeability, the team found.

Neurons grown from stem cells from people with Angelman syndrome have different properties depending on how much of the 15q11-13 region is affected, the team found in work presented in their second poster, suggesting that UBE3A is also not the whole story.

Cells carrying a complete deletion of the region are more excitable and have more atypical synaptic activity than those that have only a loss-of-function mutation in UBE3A, the researchers demonstrated.

“The other genes are clearly involved,” Levine says.

IIn addition to UBE3A, the 15q11-13 region contains genes encoding a receptor for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Unlike UBE3A, these genes are expressed from both the maternal and paternal copies. And because many people with dup15q syndrome also have epilepsy, the team speculated that something could be wrong with this receptor, which is targeted by many antiepileptic drugs.

Decreasing the expression of the GABRB3 receptor subunit using an ASO turned off the hyperexcitability of dup15q neurons. And doing the same in the neurons of people with Angelman syndrome improved their problems with inhibitory transmission but didn’t affect other properties of the cell, leading the team to believe that reduced GABRB3 expression is at least partially responsible for the synaptic changes seen in the cell. Angelman syndrome. neurons.

Normalizing receptor levels during development may give neurons “the opportunity to try and develop in a more typical way,” says Deepa Anjan Kumar, a graduate student in Levine’s lab who presented the work. But, he says, the results are preliminary and need to be confirmed.

The findings suggest that scientists will need to target genes other than UBE3A to address the full spectrum of traits seen in the conditions, says Anjan Kumar.

This may have other benefits as well. For one thing, normalization of UBE3A levels needs to happen early in development to have a strong effect, says Levine. But targeting other genes, such as those that encode GABA-A subunits, he says, may be helpful later in development.

The team plans to investigate how the expression of two other GABA-A subunits – as well as other genes within the 15q11-13 region – contributes to neuronal function. If they can identify genes other than UBE3A that contribute to the condition’s phenotypes, researchers could develop better mouse models to translate treatments, Levine says.

Laws more reports from Neuroscience 2022.

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