SNAREopathies. This post continues the series on SNAREopathies, a group of neurodevelopmental conditions caused by variants in genes encoding components that form the SNARE complex and regulatory proteins. As previously described, the SNARE complex is the molecular machinery driving synaptic vesicle release in the presynapse, which enables communication between neurons. Here, we expand the discussion to the second t-SNARE protein of the SNARE core complex, STX1A, and provide a brief review of the recent paper implicating STX1A in epilepsy and neurodevelopmental disorders.
Figure 1. Simplified representation of syntaxin 1, which is encoded by STX1A and STX1B, in the SNARE core complex and interaction with MUNC18 to enable vesicle release in the presynapse. In a recent paper, Luppe and collaborators describe ultra-rare variants in STX1A as causative etiologies in eight individuals with neurodevelopmental disorders with and without epilepsy. Through in silico analyses, the authors hypothesize that missense variants affect the interaction of syntaxin with MUNC18 and is associated with epilepsy, whereas protein-truncating variants affect the interaction of syntaxin with other core components of the SNARE complex and is associated with a neurodevelopmental phenotype without epilepsy.
STX1A. When our gene timeline came out earlier this year, STX1A had not yet been implicated in a monogenic disorder. However, in a recent paper, Luppe and collaborators describe eight individuals with ultra-rare variants in STX1A presenting with a spectrum of neurodevelopmental conditions. All individuals had intellectual disability ranging from moderate to profound. Half had epilepsy that spanned from rolandic epilepsy to epileptic encephalopathy, and one individual had West Syndrome that progressed to Lennox-Gastuat Syndrome. The spectrum of other clinical features associated with STX1A included neonatal hypotonia, resembling conditions such as spinal muscular atrophy and PURA-related disorders, movement disorders which have been associated with STXBP1, and aggression and autism increasingly recognized in individuals with SYNGAP1-related disorders.
Genetics. The variant spectrum of STX1A, which has a pLI = 0.98, included one homozygous splice variant, two de novo deletions of a single amino acid, and three de novo missense variants, of which the recurrent p.Cys145Trp variant was identified in two individuals with a consistent phenotype. Notably, all individuals with missense variants in STX1A presented with epilepsy, while individuals with deletions or splice variant had neurodevelopmental disorders without epilepsy. What is the underlying mechanism that may explain this? Answering this question requires understanding the role of STX1A in the SNARE complex.
Mechanisms. STX1A encodes syntaxin 1, which adopts two conformation states when interacting with the STXBP1 protein, or MUNC18, in vesicle exocytosis: the ‘closed’ and ‘open’ conformation. In the ‘closed’ conformation, syntaxin is bound to MUNC18 and is inaccessible to other molecules in the SNARE complex. MUNC13 then disinhibits the complex of MUNC18 and syntaxin 1 and enables the interaction with VAMP2. Therefore, Luppe and collaborators propose two mechanistic hypotheses that may explain the dichotomy. First, the authors hypothesize that the missense variants in STX1A result in steric clashes, which destabilize the syntaxin protein and weakens the interaction with MUNC18 in the ‘closed’ conformation. Second, the splicing variant and deletions are predicted to affect the formation and stability of the SNARE complex, thus altering the ‘open’ conformation. Taken together, the authors suggest that missense variants affecting the syntaxin-STXBP1 interaction is associated with epilepsy, whereas protein-truncating variants that destabilized the SNARE complex is associated with intellectual disability and a primarily neurodevelopmental phenotype.
STX1B. What more do we know about syntaxin 1? It has been previously recognized that syntaxin 1 has two brain expressed isoforms – STX1A and STX1B, which encode syntaxin 1A and syntaxin 1B respectively. In contrast to STX1A, the role of STX1B in epilepsy and neurodevelopmental disorders had previously been described in 49 individuals, including a GEFS+ phenotype in 31 individuals, developmental and epileptic encephalopathy in 15, GGE in 2, and focal epilepsy in 2 individuals. Interestingly, missense variants were associated with a more severe phenotype including 86% of individuals with DEEs, while protein-truncating variants were associated with a GEFS+ phenotype. How does this all come together with thinking about STX1B in the context of STX1A?
Homology. Similar to sodium channel genes implicated in epilepsy, STX1A and STX1B share high homology. Luppe and collaborators describe an individual with the STX1A variant p.Cys145Trp with a severe DEE phenotype and additional features including cerebellar ataxia and spasticity; the homologous residue in STX1B (p.Cys144Phe) was previously identified in an individual with a DEE phenotype with ataxia, pointing to high paralog conservation and likely corresponding functional role within this region. However, consistent with established SNAREopathies, a high degree of phenotypic heterogeneity is also observed, with a relatively less severe course of GEFS+ in the majority of individuals with STX1B-related disorders, possibly due to genetic redundancy with STX1A. Further investigation will be critical to understand the underlying basis of heterogeneity between STX1A and STX1B – and between the broader group of SNAREopathies.
What you need to know. SNAREopathies refer to a group of neurodevelopmental conditions with a shared mechanistic basis in the presynapse. Variation in established genes such as SNAP25 and STXBP1 are increasingly recognized as etiologies in pediatric epilepsy. In a recent study, Luppe and collaborators provide clinical and genetic evidence that support STX1A as the causative gene of a novel neurodevelopmental disorder, with a broad spectrum of symptoms that both overlap with and are distinct from other SNAREopathies. Further characterization of STX1A-related disorders and investigation of the molecular basis will be essential to identify therapeutic targets and contribute to the growing knowledge of SNAREopathies more broadly.
This post was co-written by Julie Xian and Kim Marie Thalwitzer.
Julie Xian is a Data Scientist in the Helbig Lab at Children’s Hospital of Philadelphia (CHOP).
