STXBP1 encephalopathies: Clinical spectrum, disease mechanisms, and therapeutic strategies

Abstract

Mutations in Munc18-1/STXBP1 (syntaxin-binding protein 1) are linked to various severe early epileptic encephalopathies and neurodevelopmental disorders. Heterozygous mutations in the STXBP1 gene include missense, nonsense, frameshift, and splice site mutations, as well as intragenic deletions and duplications and whole-gene deletions. No genotype-phenotype correlation has been identified so far, and patients are treated by anti-epileptic drugs because of the lack of a specific disease-modifying therapy. The molecular disease mechanisms underlying STXBP1-linked disorders are yet to be fully understood, but both haploinsufficiency and dominant-negative mechanisms have been proposed. This review focuses on the current understanding of the phenotypic spectrum of STXBP1-linked disorders, as well as discusses disease mechanisms in the context of the numerous pathways in which STXBP1 functions in the brain. We additionally evaluate the available animal models to study these disorders and highlight potential therapeutic approaches for treating these devastating diseases.

Keywords: Munc18-1; STXBP1; encephalopathy; epilepsy; synapse; therapeutic approaches.

FIGURE 1

Phenotypic spectrum of all known STXBP1 patients. (a) Patients were categorized by their final clinical diagnosis (green = non-epileptic syndromes; blue = epileptic syndromes). (b–g) Phenotypic spectra subcategorized by mutations. Final patient diagnoses were separated by type of mutation into (b) missense mutations, (c) nonsense mutations, (d) frameshift mutations, (e) splice site mutations, (f) intragenic deletions/duplications, and (g) whole-gene deletions (ASD, autism spectrum disorder; ATR, ataxia-tremor-retardation syndrome; ID, intellectual disability; EE, epileptic encephalopathies; EOEE, early onset epileptic encephalopathy)

FIGURE 2

Proposed functions of STXBP1 within a neuron. Yellow boxes highlight cellular processes that mutations in STXBP1 may affect: Degradation (1) or promiscuous SNARE-complex formation (2) of syntaxin-1 during biosynthesis because of lack of STXBP1 binding (3); trafficking of syntaxin-1 from the ER to the Golgi (4) and to the synapse (5, 6); synaptic SNARE-complex formation with SNAP-25 and synaptobrevin-2/VAMP2 (7) and neurotransmitter release (8), via binding to rab3, Doc2, Mint1/2, and syntaxin-1 (9; note that the arrows here indicate experimental evidence for binding only); possibly SNARE-complex formation responsible for post-synaptic receptor trafficking (10). Note that the interaction of STXBP1 with syntaxin-1 and its effect on neurotransmitter release is the most established interaction, whereas the others have not been investigated to that detail. Yet, for completeness, these interactions are included here as well

FIGURE 3

Disease-causing missense mutations in STXBP1. Top: Primary sequence of STXBP1 with indication of its domain structure and positions of disease-linked missense mutations. Bottom: Localization of disease-causing missense mutations of STXBP1 in its tertiary structure (PDB code 4JEU1 (Colbert et al. 2013)). Mutated residues are highlighted in magenta in three different views. Protein structure images were generated using the PDB file and PyMOL (Schrödinger)