Single gene insufficient to account for dup15q, Angelman traits

November 22, 2022

Single gene insufficient to account for dup15q, Angelman traits

 

BY ANGIE VOYLES ASKHAM  /  Spectrum News / 18 NOVEMBER 2022

 

Multiple genes shape the traits of the autism-linked conditions dup15q syndrome and Angelman syndrome, according to two new unpublished studies.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 the 15q11-13 chromosomal region, whereas dup15q syndrome stems from duplications of it. Although 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 been considered an important target for dup15q syndrome as well. Over- or under-expression of the maternal, but not paternal, 15q11-13 region leads to one or the other of the two conditions — clueing researchers in to the idea that UBE3A, which is silenced on the paternal copy through imprinting, is at fault.

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

But which traits stem from atypical expression of UBE3A, and which other genes might be involved, has been unclear, says Marwa Elamin, a postdoctoral fellow in Eric Levine’s lab at the University of Connecticut School of Medicine in Farmington, who presented one of the posters.

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

The findings have important implications for the development of treatments, says Ben Philpot, 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 might also provide therapeutic benefit.”

Neurons grown from stem cells of people with dup15q syndrome fire more spontaneous action potentials than do control neurons that have the same genetic background but no extra chromosomal region, the researchers