Strides in STXBP1: What Happened Last Month in STXBP1 Research?
So, what was new in February 2024?
A group of researchers at Vrije University in Amsterdam, led by Matthijs Verhage, who is on the Foundation’s Scientific Advisory Board, published a paper looking at patient-derived neurons from STXers with a variety of different mutations. They examined several different features of these neurons and while they found that neurons from all STXBP1 individuals had similar decreases in the amount of STXBP1 protein and RNA and had showed dysregulation of other synapse-related proteins and altered electrical activities, they found some distinctive differences that suggested the patients could be separated into two different subgroups; these subgroups were not based on the type of STXBP1 gene mutation (i.e. nonsense, missense, splice site mutation). These findings may help explain why symptoms can be so different between individuals with STXBP1-RD. This research was partly funded by the STXBP1 Foundation through the Orphan Disease Center and the Million Dollar Bike Ride.
Learning and memory formation in the brain is associated with structural changes in synapses caused by the interworking of several different proteins, including proteins known as phospholipases and the generation of molecules known as saturated free fatty acids (FFAs). A group from Australia examined one such phospholipase, called DDHD2, and found that mice lacking this gene have severe memory and cognitive disabilities associated with decreases in saturated FFAs. They then discovered that STXBP1 binds to DDHD2 and transports it to the synapse membrane and that mice with STXBP1 mutations also show abnormal changes in saturated FFAs. These findings may help to explain some of the cognitive impairments observed in STXBP1-RD.
Mingshan Xue’s lab a Baylor College of Medicine published their findings in mice where the selectively mutated the Stxbp1 gene in GABAergic or Glutamatergic neurons and examined differences in mouse behavior. They found that mutations in GABAergic neurons, which have more inhibitory influences in the brain, mediate the majority of symptoms observed in STXBP1-RD compared to glutamatergic neurons, which have more of an excitatory influence in the brain. This research was presented is a poster format at the Foundation’s 2022 Summit+ meeting and has been further summarized in a previous blog post here.
If you read this blog for January you may recall that Chinese researches demonstrated that STXBP1 was involved in the release of what are called extracellular vesicles (EVs). EVs are used by cells to communicate with one another and are thought to be involved in numerous biological processes. This month, a Swedish group published similar findings, showing that STXBP1 is involved in EV release, and further demonstrated that an inflammatory response mediated by EVs is decreased in Stxbp1+/- mutant mice and normal mice where the Stxbp1 RNA is inhibited. These findings further the idea that STXBP1 is involved in more than just neuronal functions.
A group in Portugal examined 46,000 disease-associated de novo mutations. De novo mutations (DNMs) are variants that occur in a child but is not inherited from the parents; almost all cases of STXBP1-RD are due to DNMs. Of the 13,277 human genes with DNMs that they examined, the STXBP1 gene had the sixth highest proportion of DNMs based on gene size (i.e number of nucleotide base pairs that make up the gene).
