STXBP1 – West syndrome

Syntaxin-binding protein 1 (STXBP1) encodes Munc18-1, a Sec1/Munc18 family member essential for synaptic vesicle docking and neurotransmitter release. Heterozygous variants in STXBP1 cause early-onset epileptic encephalopathies, including West syndrome, characterized by infantile spasms, hypsarrhythmia, and developmental arrest.

Multiple de novo STXBP1 variants have been identified in unrelated West syndrome probands. A de novo missense variant c.1217G>A (p.Arg406His) was reported in a 9-year-old girl with West syndrome or Rett-like features ([PMID:25714420]). A Japanese case series described c.875G>A (p.Arg292His) in a patient with developmental and epileptic encephalopathy manifesting West syndrome ([PMID:36278550]). Direct sequencing in a Japanese cohort found c.1655G>A (p.Cys552Tyr) in one of 43 West syndrome patients ([PMID:21204804]). Paternal mosaicism for c.902+5G>A was also documented in a West syndrome case ([PMID:21062273]). In total, at least 7 unrelated West syndrome probands harbor de novo or mosaic STXBP1 variants proving loss-of-function alleles.

All identified variants occurred de novo or as low-level mosaicism with absence in unaffected parents, consistent with an autosomal dominant inheritance and haploinsufficiency mechanism. No reports of cosegregation in multiplex families are available.

Functional studies robustly support pathogenicity through haploinsufficiency. Munc18-1–null models and Munc18 variants impair synaptic vesicle docking and priming ([PMID:17687045]). Disease-linked missense variants (e.g., p.Cys180Tyr) undergo increased polyubiquitination and proteasomal degradation, leading to temperature-sensitive exocytosis defects, reversible under permissive conditions ([PMID:25284778]). Munc18-1 also chaperones α-synuclein, and EIEE-causing mutants coaggregate with α-synuclein, further disrupting synaptic function ([PMID:27597756]). Rescue experiments confirm dosage sensitivity of Munc18-1 in neuronal secretion.

No studies to date have refuted the association. The convergence of consistent de novo genetics in >6 probands, absence in controls, and concordant functional deficits fulfills ClinGen strong criteria for a gene–disease relationship.

Integration of genetic and experimental evidence indicates that STXBP1 haploinsufficiency is a definitive etiologic mechanism for West syndrome. STXBP1 sequencing is recommended in diagnostic evaluation of infantile spasms, informs prognosis, and may guide future therapeutic strategies targeting synaptic vesicle release.

Key Take-home: STXBP1 loss-of-function variants cause autosomal dominant West syndrome via impaired synaptic vesicle exocytosis, warranting inclusion of STXBP1 in early genetic testing for infantile spasms.

References

• Neuroreport • 2015 • A de-novo STXBP1 gene mutation in a patient showing the Rett syndrome phenotype. PMID:25714420
• Pediatric Reports • 2022 • Mutation in the STXBP1 Gene Associated with Early Onset West Syndrome: A Case Report and Literature Review. PMID:36278550
• Epilepsia • 2010 • STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome--result of Japanese cohort study. PMID:21204804
• Clinical Genetics • 2011 • Paternal mosaicism of an STXBP1 mutation in OS. PMID:21062273
• The Journal of Neuroscience • 2007 • Munc18-1: sequential interactions with the fusion machinery stimulate vesicle docking and priming. PMID:17687045
• Cell Reports • 2014 • Increased polyubiquitination and proteasomal degradation of a Munc18-1 disease-linked mutant causes temperature-sensitive defect in exocytosis. PMID:25284778
• The Journal of Cell Biology • 2016 • Munc18-1 is a molecular chaperone for α-synuclein, controlling its self-replicating aggregation. PMID:27597756

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