Strides in STXBP1 April
So, what’s new in April of 2025?
Two review articles were published by research collaborators of the Foundation. Review articles are not focused on new discoveries but instead provide a broad overview of a topic to help researchers and the public understand key concepts.
One review, led by Mingshan Xue and his colleagues at Baylor, explored how genetic mutations affecting the presynapse can lead to epilepsies. The release of neurotransmitters from synaptic vesicles in the presynapse involves 3 main steps: loading a vesicle with neurotransmitters and making them available for release (vesicle pool regulation); fusion of the vesicle with cell membrane and release of the neurotransmitter (vesicle fusion); and recovery of the empty vesicle so it can be refilled and reused (vesicle recycling). These steps are carried out by many different proteins. The review highlighted three important proteins involved in these steps: Synapsin1, STXBP1, and Dynamin1, and examined how mutations in these genes contribute to epilepsy and neurodevelopmental disorders.
Another review led by Francisco Esteban team in Spain, provided a broad overview of STXBP1-RD including pathology and symptoms and various therapeutic approaches that are currently under investigation. Their paper also outlined plans to use whole genome sequencing on a large group of Spanish individuals with STXBP1-RD to identify additional genetic factors that might explain the variation in symptoms seen across affected individuals. Their work could help uncover new insights into the complexity of these disorders and guide future treatments.
Epilepsy that starts before the age of 5 is called early-onset epilepsy. A group of researchers from Greece used a bioinformatics approach to identify genes that significantly impacted the development of EOE. They originally identified 229 important genes linked to EOE that are active in the brain. By analyzing these genes, they found connections to several key brain functions, including addiction pathways (like nicotine and morphine addiction), how brain cells communicate, and how the brain maintains proper electrical balance. Through further analysis, they identified 12 central genes, with seven standing out as especially important in understanding EOE. These seven genes included CDKL5, GABRA1, KCNQ2, KCNQ3, SCN1A, SCN8A, and STXBP1. The researchers argued that treatments that specifically interact with these genes may be most beneficial in treating EOE.
A study somewhat similar to the above EOE study was carried out by investigators from China who were looking for genes that had an impact on the progression of Parkinson’s disease (PD). One key feature of PD is the build up of clumps called Lewy bodies inside brain cells; these Lewy bodies are made up primarily of a protein called alpha-synuclein. The spread and increase in Lewy bodies in the brain, and thus the progression of PD is defined in what are called Braak stages. The researchers screened 388 genes that were associated with Braak stages and identified 8 hub genes that stood out as playing a significant role, one of those genes is STXBP1, which had decreased expression in some PD Braak stages. Interestingly, previous studies have suggested that STXBP1 protein can bind to alpha-synuclein and may act as a molecular chaperone. A decrease in STXBP1 protein expression in PD could lead to less protein available to chaperone alpha-synuclein thus allowing alpha-synuclein to self-aggregate into Lewy bodies.
Researchers in Peru examined 124 children (ages 5-18) diagnosed with intellectual disability (ID) to determine if genetic variants could be attributed as a cause. They found variants in 38 of children (30.6%) and of these 38, two of the children (5.2%) had variants in the STXBP1 gene, making it one of the top 3 genes associated with ID in this population. The findings emphasize the need for genetic testing in cases of childhood ID.
