Strides in STXBP1: What Happened Last Month in STXBP1 Research?
What Happened Last Month in STXBP1 Research?
Hey there. Welcome to our news round-up, where we talk about what happened in STXBP1 research in the previous month. Even though STXBP1 is not common, scientists from all around the world are working really hard to understand the gene, protein, and disorder better. Every month, they publish research papers about STXBP1, and in this news round-up, we'll share some interesting things they found out.
So, what was new in March 2024?
Drs Ben Prosser and Mike Boland, both STXBP1 dads and members of the Foundation’s Scientific Advisory Board, were co-authors along with another researcher on a paper that described the work being done at the Center for Epilepsy and Neurodevelopmental Disorders (ENDD) to develop new therapies for STXBP1. These include drug repurposing, ASOs, gene replacement, premature stop readthrough, and CRISPR activation. They discussed why it is important to develop a wide range of different therapies – not every therapy may be appropriate for every STXer due to differences in symptoms and/or STXBP1 variant type. They also discussed some of the research tools they are using to help in the development of these therapies, which include patient-derived iPSCs and a mouse model where the mouse’s Stxbp1 gene has been replaced by the human STXBP1 gene.
As you know, STXBP1-RD is caused by having one mutant, or variant, copy of the STXBP1 gene, which ends up causing a decrease in synapse function. Dr Matthijs Verhage’s group at Vrije University in Amsterdam reported on a unique disease-causing STXBP1 variant, L446F that appears to work differently. This variant, which is a missense variant, is unique because two siblings with epilepsy have been found who are homozygous for this variant. This means that the siblings have two mutant copies of the STXBP1 gene. All other known cases of STXBP1-RD are caused by having a single mutant copy of the gene. Interestingly the mother and another sibling only have one copy of the L446F variant and are disease-free. By generating both mouse and human neurons in the lab that contain two copies of the L446F variant the researchers were able to demonstrate that instead of decreasing synapse function, having two copies of this variant actually increases synapse function and thus causes over-excitability.
The Vrije University Amsterdam group together with another researcher group at Heidelberg University in Germany published their findings on 11 different STXBP1-causing variants and 5 non-disease-causing (neutral) variants of the STXBP1 gene. They found that all 11 STXBP1-causing variants, but not the 5 neutral variants, produced STXBP1 protein that was less stable and tended to lose its normal shape, and thus function, at body temperature. They did not observe any clumping or aggregation of the produced protein, which has been proposed as another explanation for how STXBP1 variants could cause disease. The team also developed an algorithm, PRESR, that can help predict if any given STXBP1 missense variant would be disease-causing or neutral.
Late last year, before this new newsletter feature began, scientists from the University of Copenhagen published a paper describing how mutations in STXBP1 can cause increased excitability in the cortex of the brain that may lead to epilepsy. They found that the inhibitory neurons in the brain of Stxbp1 mice, that normally stop the excitatory neurons from becoming overexcited, do not function properly and therefore are unable to properly inhibit the excitatory neurons. This past month, the group published another paper that detailed how they ‘electrically recorded’ from the mouse neurons in order to provide a guide for other scientists who may want to do the same thing.
