Single gene deficient for dup15q, Angelman traits |  Spectrum |  Autism research news

Single gene deficient for dup15q, Angelman traits | Spectrum | Autism research news

Your browser does not support the video tag.

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

Multiple genes shape characteristics of the autism-related disorders dup15q syndrome and Angelman syndrome, according to two new unpublished studies.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, while dup15q syndrome is due to duplications thereof. Although the characteristics for the two disorders are different – dup15q is more likely to lead to autism, for example – both syndromes are associated with an increased likelihood of seizures and developmental delays.

Researchers have long suspected that a single gene in the region, UBE3A, drives Angelman syndrome, and it has also been implicated as an important target for dup15q syndrome. Over- or under-expression of the maternal but not the paternal 15q11-13 region leads to one or the other of the two conditions – leading the researchers to the idea that UBE3A, silenced by imprinting on the paternal copy, there is error.

People with Angelman syndrome who lose 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 the traits associated with this condition.

But which features result from the atypical expression of UBE3A and which other genes might be involved is unclear, says Marwa Elamin, a postdoctoral researcher 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 features seen in neurons carrying dup15q and Angelman syndrome mutations.

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

NOTEurons grown from stem cells from people with dup15q syndrome fire more spontaneous action potentials than control neurons, which have the same genetic background but no additional chromosomal region, the researchers previously reported. This type of extra activity could lead to the seizures seen in people with the condition, the team suspect.

Dup15q neurons also have reduced inhibitory postsynaptic currents and a more permeable cell membrane, the team found in the study presented by Elamin, which is also available as an unpublished preprint. Lowering UBE3A expression using an antisense oligonucleotide (ASO), a short strand of RNA capable of modifying protein expression, normalizes the cells’ spontaneous activity and intrinsic excitability, but does not alter their membrane permeability.

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

To replicate the same excess of UBE3A without overexpressing other genes within the 15q11-13 region, Elamin and her colleagues used neurons derived from an individual who has two copies of UBE3A on their paternal chromosome and used an ASO to disable those copies. Overexpression of UBE3A replicated the intrinsic hyperexcitability observed in dup15q cells, but not altered 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 the work presented in their second poster, suggesting suggesting that UBE3A isn’t the whole story there either.

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

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

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

Reducing expression of the GABRB3 receptor subunit using an ASO reduced the hyperexcitability of dup15q neurons. And doing the same in neurons from people with Angelman syndrome exacerbated their problems with inhibitory transmission but did not affect other properties of the cell – leading the team to suggest that reduced expression of GABRB3 might be at least partly responsible for the Syndrome observed synaptic changes is responsible neurons.

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

The results suggest scientists need to target genes other than UBE3A to capture the full range of traits observed in the conditions, says Anjan Kumar.

This can have other benefits as well. For one, normalizing UBE3A levels must occur early in development to have a strong effect, Levine says. But targeting other genes, like those that code for the GABA-A subunits, could be beneficial later in development, he says.

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

Read more reports from Neuroscience 2022.

#Single #gene #deficient #dup15q #Angelman #traits #Spectrum #Autism #research #news

Leave a Comment

Your email address will not be published. Required fields are marked *