TY - JOUR
T1 - De novo STXBP1 mutation in a child with developmental delay and spasticity reveals a major structural alteration in the interface with syntaxin 1A
AU - Banne, Ehud
AU - Falik-Zaccai, Tzipora
AU - Brielle, Esther
AU - Kalfon, Limor
AU - Ladany, Hagay
AU - Klinger, Danielle
AU - Schneidman-Duhovny, Dina
AU - Linial, Michal
N1 - Publisher Copyright:
© 2020 Wiley Periodicals LLC.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - STXBP1, also known as Munc-18, is a master regulator of neurotransmitter release and synaptic function in the human brain through its direct interaction with syntaxin 1A. STXBP1 binds syntaxin 1A is an inactive conformational state. STXBP1 decreases its binding affinity to syntaxin upon phosphorylation, enabling syntaxin 1A to engage in the SNARE complex, leading to neurotransmitter release. STXBP1-related disorders are well characterized by encephalopathy with epilepsy, and a diverse range of neurological and neurodevelopmental conditions. Through exome sequencing of a child with developmental delay, hypotonia, and spasticity, we found a novel de novo insertion mutation of three nucleotides in the STXBP1 coding region, resulting in an additional arginine after position 39 (R39dup). Inconclusive results from state-of-the-art variant prediction tools mandated a structure-based approach using molecular dynamics (MD) simulations of the STXBP1–syntaxin 1A complex. Comparison of the interaction interfaces of the wild-type and the R39dup complexes revealed a reduced interaction surface area in the mutant, leading to destabilization of the protein complex. Moreover, the decrease in affinity toward syntaxin 1A is similar for the phosphorylated STXBP1 and the R39dup. We applied the same MD methodology to seven additional previously reported STXBP1 mutations and reveal that the stability of the STXBP1–syntaxin 1A interface correlates with the reported clinical phenotypes. This study provides a direct link between the outcome of a novel variant in STXBP1 and protein structure and dynamics. The structural change upon mutation drives an alteration in synaptic function.
AB - STXBP1, also known as Munc-18, is a master regulator of neurotransmitter release and synaptic function in the human brain through its direct interaction with syntaxin 1A. STXBP1 binds syntaxin 1A is an inactive conformational state. STXBP1 decreases its binding affinity to syntaxin upon phosphorylation, enabling syntaxin 1A to engage in the SNARE complex, leading to neurotransmitter release. STXBP1-related disorders are well characterized by encephalopathy with epilepsy, and a diverse range of neurological and neurodevelopmental conditions. Through exome sequencing of a child with developmental delay, hypotonia, and spasticity, we found a novel de novo insertion mutation of three nucleotides in the STXBP1 coding region, resulting in an additional arginine after position 39 (R39dup). Inconclusive results from state-of-the-art variant prediction tools mandated a structure-based approach using molecular dynamics (MD) simulations of the STXBP1–syntaxin 1A complex. Comparison of the interaction interfaces of the wild-type and the R39dup complexes revealed a reduced interaction surface area in the mutant, leading to destabilization of the protein complex. Moreover, the decrease in affinity toward syntaxin 1A is similar for the phosphorylated STXBP1 and the R39dup. We applied the same MD methodology to seven additional previously reported STXBP1 mutations and reveal that the stability of the STXBP1–syntaxin 1A interface correlates with the reported clinical phenotypes. This study provides a direct link between the outcome of a novel variant in STXBP1 and protein structure and dynamics. The structural change upon mutation drives an alteration in synaptic function.
KW - Munc-18
KW - SNARE proteins
KW - epileptic encephalopathies
KW - molecular dynamics
KW - synaptic pathology
KW - syntaxin
UR - http://www.scopus.com/inward/record.url?scp=85089534311&partnerID=8YFLogxK
U2 - 10.1002/ajmg.b.32816
DO - 10.1002/ajmg.b.32816
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C2 - 32815282
AN - SCOPUS:85089534311
SN - 1552-4841
VL - 183
SP - 412
EP - 422
JO - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
JF - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
IS - 7
ER -