Information for clinicians
We are continuously working to gather more information on STXBP1 mutations, both those identified in patients as well as in asymptomatic individuals. We are already in contact with physicians treating STXBP1-carrier patients world-wide. If you have (a) patient(s) carrying a STXBP1-mutation, we would be very happy if you would get in touch with us. You can do so using this email address: email@example.com
Our aim is to gather and summarize all currently known information about STXBP1 patients. This includes information on clinical symptoms that are experienced by patients, but also genetic data and EEG measurements (if available). In addition to this, we intend to study the molecular and cellular effects of pathological STXBP1 mutations. This can be achieved through the expression of mutant STXBP1 in rodent cells or in iPSC-derived human neurons.
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 more elaborate background on the molecular mechanisms of this protein please follow this link or go to ‘Information for researchers’.
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 we also show in our paper Kovačević et al. 2018.
One of the main goals of our research is to understand how genetic mutations in STXBP1 lead to the clinical symptoms. Please visit our research page for more information.
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 our research team. For more elaborate information on MUNC18-1’s functions please follow this link or go to ‘Information for researchers’.
Our research at VU Amsterdam
Our research at the Functional Genomics Department at the Vrije Universiteit (VU) Amsterdam and Amsterdam medical center (Amsterdam UMC) has focused for many years on understanding the function of STXBP1/MUNC18-1 in nerve cells.
We have used experimental mouse and cell models in which STXBP1/MUNC18-1 protein cannot be produced due to genetic modifications that alter the STXBP1 gene in such a way that the gene cannot produce the protein (‘knock out’ technology; see figure on the left). It is important to note that these models do not exactly mimic the situation in (human) patients. Patients carry one healthy STXBP1 gene
copy and one copy with a mutation, while in knock out mice and neurons both copies are defective. However, studies using these mouse and cellular models provide invaluable information on the function of STXBP1 in the brain. We have unraveled how STXBP1/MUNC18-1 organizes the initial docking of transmitter vesicles at the synapse, how it helps to prepare vesicles for fusion with the plasma membrane and with which other proteins it collaborates to do this. We have also discovered several pathways that modulate these functions of STXBP1/MUNC18-1, promoting or inhibiting its role in synaptic transmission. Please visit our research page to find out more detailed information about what our lab discovered on the function of STXBP1/MUNC18-1.
Translational approaches to STXBP1-E
We have recently published a scientific paper where we present a mouse model that recapitulates the clinical symptoms seen in patients carrying a STXBP1 mutation.
In this paper, we first provide evidence that haploinsufficiency is the most likely explanation for STXBP1-E. We show that disease-causing mutations in STXBP1 lead to reduced stability of the STXBP1 protein in nerve cells. Next, we have modeled haploinsufficiency in mice by heterozygous deletion of STXBP1. This means that one of the gene copies of STXBP1 is disabled, leaving only one healthy copy. Seizures, tonic spasms (especially during sleep) and EEG-abnormalities observed in patients with STXBP1-E are all observed in these mice. The anti-epileptic drug levetiracetam, often subscribed to STXBP1-E patients, suppressed these symptoms. In addition, these mice displayed cognitive impairments and hyperactivity. Overall, our study shows that heterozygous deletion of STXBP1 in mice provides a valid model for the development of therapeutic interventions for STXBP1-E.
For current research lines on STXBP1-E see the bottom of this page.