STXBP1 Research
The following information serves to give background on the genetic causes and potential disease mechanisms of STXBP1 Encephalopathy as well as a brief description of the functions of the protein that is encoded by STXBP1, MUNC18-1.
For information on current research projects, see Ongoing studies page.
STXBP1 Encephalopathy is caused by mutations in the gene STXBP1
Genes contain the genetic code to produce proteins. The STXBP1 gene encodes the STXBP1 protein, more commonly known as MUNC18-1. Proteins like MUNC18-1 are the molecules to make our cells and tissues work. Mutations in genes often lead to the production of abnormal proteins that cannot perform their normal function. In some cases, the effects of mutations are really subtle and the mutant protein functions almost as well as the normal protein, but in other cases the protein is not even produced at all.
In addition to the genetic code to produce a protein, genes also contain much more code, for instance, information on when to produce protein during development and/or in adulthood. This ‘non-protein-coding’ code instructs our cells to produce, for example, the MUNC18-1 protein in all nerve cells of the brain, already during early (prenatal) development until old age.
Hence, only a fraction of a gene’s genetic code encodes a protein. Most of the code is there to guide protein production and for much of the code we actually do not yet understand the function. In the case of STXBP1, mutations that cause STXBP1 Encephalopathy are usually located inside the part of the gene that encodes the protein and are found across the whole length of the gene (see figure above). In addition, mutations in the STXBP1 genetic code that does not encode the protein have also been linked to disease, especially autism, but these links are still poorly understood. Finally, several other links between STXBP1/MUNC18-1 function and brain disease have been reported, for instance, with schizophrenia and Alzheimer’s disease. Understanding such links to other diseases is one of the aims of our research.
Haploinsufficiency: A likely disease mechanism
Mutations that are predicted to have mild effects on the protein’s function (mild impact) occur just as well as mutations where no protein is predicted to be made at all (severe impact). Based on the clinical information currently available, mutations with predicted mild or severe impact can lead to the same disease severity and there is no evidence that certain symptoms are associated with one or the other. However, a more systematic comparison between predicted impact and patient symptoms is required. It is our ambition to contribute to such systematic comparisons.
In cases where mild and severe impact mutations lead to the same disease, it is often the case that a protein that was produced from the mutated copy of the gene is not stable and is rapidly degraded inside our cells.
This means that there is less protein available for the cell, as only half of the usual amount of protein is kept - the part that was produced by the healthy copy of the gene. The situation where one healthy copy of a gene is not enough to maintain healthy functioning is called ‘haploinsufficiency’. In the case of STXBP1 Encephalopathy, this would mean that half of the usual amount of MUNC18-1 protein is not enough for its normal function in our nerve cells and that this may be responsible for the disease. Haploinsufficiency was already proposed as a likely scenario in the first paper on STXBP1 Encephalopathy and is still the most likely explanation for the disease, as is also shown in the paper by Kovačević et al. 2018.
The biological function of the MUNC18-1 protein
Thousands of different proteins, encoded by thousands of genes, are present in every nerve cell (neuron) of our brain. Proteins are essential for the structure, maintenance and functionality of neurons. For a neuron, one of the main tasks is to receive and send information to other neurons and to integrate information coming from different sources (other neurons, for example, in sensory organs). This communication and integration is a central aspect in the way we think, feel and move.
STXBP1 has an essential function in neuronal communication
Neuronal communication happens at specialized contact points between neurons, called synapses. It has been estimated that we have around 100 billion synapses in our brain. At each synapse, the ‘sending’ neuron conveys a message to the ‘receiving’ neuron. This works via the release of vesicles that are filled with signalling molecules, generally known as neurotransmitters. Once arriving at the receiving neuron, the neurotransmitters evoke a reaction in this cell, meaning that the message has been conveyed successfully. Within this process, many proteins work together at each step of the way. The MUNC18-1 protein, for example, plays an essential role in the fusion of the neurotransmitter-filled vesicles. Indeed, without this protein, neuronal communication cannot take place at all and no other protein can make up for this loss. In addition, MUNC18-1 has other functions in neurons and possibly in other cell types in our body. Understanding the biological functions of this protein has been a long term goal of several of our research teams.