Heterozygous variants in the STXBP1 gene are responsible for a form of early-onset epileptic encephalopathy (EIEE4; OMIM 612164) highlighted by epilepsy and often severe intellectual disability (Saitsu et al., 2008; Deprez et al., 2010). ASD has been observed in individuals with STXBP1 variants both in the presence and absence of epilepsy and/or intellectual disability (Campbell et al., 2012; Neale et al., 2012; Deciphering Developmental Disorders Study, 2015; Yuen et al., 2015; Wang et al., 2016). A systemic review of 147 patients with STXBP1 encephalopathy, including 45 previously unreported patients, demonstrated that autism or autistic features were observed in approximately 20% of published cases, although the actual number of cases with autism/autistic features may be greater due to the focus of most studies on the intellectual disability/epilepsy phenotype (Stamberger et al., 2016). Variants in STXBP1 have also been identified in patients presenting with atypical Rett syndrome, with affected individuals frequently exhibiting autistic features and stereotyped movements (Romaniello et al., 2015; Olson et al., 2015). A de novo missense variant that was predicted to be deleterious (defined as having an MPC score 2) was identified in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified STXBP1 as a candidate gene with a false discovery rate (FDR) between 0.01 and 0.05 (0.01 < FDR 0.05). An additional de novo loss-of-function variant and a potentially damaging missense variant in the STXBP1 gene were identified in ASD probands from the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified STXBP1 as a gene reaching exome-wide significance (P < 2.5E-06).
Molecular Function
This gene encodes a syntaxin-binding protein. The encoded protein appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in this gene have been associated with infantile epileptic encephalopathy-4.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Novel 9q34.11 gene deletions encompassing combinations of four Mendelian disease genes: STXBP1, SPTAN1, ENG, and TOR1A.
Clinical whole exome sequencing revealed de novo heterozygous stop-gain and missense variants in the STXBP1 gene associated with epilepsy in Saudi families
Stxbp1 heterozygous mice with different genomic backgrounds recapitulate the seizure/spasm phenotype observed in humans that were rescued by the antiepileptic drug levetiracetam. Heterozygous conditional knockout mice with selective Stxbp1 deficiency in GABAergic neurons, showed increased early postnatal mortality, and seizures. Stxbp1 heterozygous mice showed impaired cognitive performance, hyperactivity and anxiety-like behavior, without altered social behavior (Kovacevic et al., 2018).
References
Type
Title
Author, Year
Primary
Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy.
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The Stxbp1^cre/+ line was created using Cre-loxP-mediated recombination in the germ line. Cre-deleter mice were crossed with Stxbp1^lox/+ mutants, which were generated on a C57BL/6J background and bred further on C57BL/6J background, generating a Stxbp1 heterozygous mouse line without flanking gene variations. .
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional heterozygous deletion of exons 2-6 (most likely, article is not clear)of the Stxbp1 gene using Gad2-cre in gabaergic neurons
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Congenic C57BL/6J Stxbp1 mice were originally generated by deleting exons 26, preventing translation after amino acid 14, in the embryonic stem cells derived from a 129S1/SvImJ strain and backcrossed to C57BL/6J mice for over 40 generations. Three genes (Card9, Rapgef1 and Dolpp1) with passenger mutations from 129SvJ genetic background were detected in the flanking genes region in congenic C57BL/6J Stxbp1 mice.
Allele Type: Knockout
Strain of Origin: 129S1/SvImJ
Genetic Background: C57BL/6J
ES Cell Line: 129S1/SvImJ
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The reverse 129Sv Stxbp1 heterozygous line was created by mating male congenic C57BL/6J Stxbp1 heterozygous mice with females of the inbred 129S1/SvImJ strain for three generations.
Allele Type: Knockout
Strain of Origin: 129S1/SvImJ
Genetic Background: 129S1/SvImJ
ES Cell Line: 129S1/SvImJ
Mutant ES Cell Line: Model Source:
Description: Mutants show decrease in proportion of overall activity duration in the phenotyper during the light phases.
Exp Paradigm: The diurnal rhythm was assessed by monitoring undisturbed behavior in an automated home-cage system (phenotyper) enriched with a shelter for three consecutive days. parameters measured included activity, dark-light ratio, habituation, kinematics, sheltering, and phase transition.
Description: Mutants show increase in proportion of activity duration during the first 3 h of the dark phase in the home-cage environment during the first dark phase. mutants show no change in overall activity during the dark phase. mutants show no change in circadian rhythm assessed by changes in the activity in anticipation of, and response to, day/night transitions and proportion of time spent outside the shelter.
Exp Paradigm: The diurnal rhythm was assessed by monitoring undisturbed behavior in an automated home-cage system (phenotyper) enriched with a shelter for three consecutive days. parameters measured included activity, dark-light ratio, habituation, kinematics, sheltering, and phase transition.
Description: Mutants twitch spontaneously, predominantly during the light or inactive phase of the murine circadian cycle, indicating an epileptic event. mutants jump spontaneously in an apparent sleep or inactive state during the light or inactive phase of the murine circadian cycle, indicating an epileptic event.
Exp Paradigm: A twitch was defined as a sudden, myoclonic jerk of the animals body from resting state (apparent sleep) that did not cause the mouse to wake. jumps were differentiated from twitches by a change in the position of the mouse in the cage and were followed by activity and sometimes accompanied by a straub tail reaction.
Electroencephalogram (eeg): signature of seizure/epilepsy1
Increased
Description: Mutants show automatic spike wave discharges (swds) during 24hr ecog recording. mutant mice showed frequent, high amplitude spike-wave discharges in both hippocampal and cortical recordings that were visually not detected in control mice.
Exp Paradigm: NA
Description: In the elevated plus maze mutant mice showed delayed latency to enter the open arms, spent less time on the open arms, and visited the open arms less frequently compared to control mice.
Exp Paradigm: NA
Description: In the dark-light box test, mutant mice showed longer latency to visit the bright compartment, spent less time in the bright compartment, and made fewer visits to the bright compartment, compared to control mice.
Exp Paradigm: NA
Description: Mutants spend less time on top of the shelter in the enriched cage compared to controls.
Exp Paradigm: Spontaneous behavior was automatically monitored for 3 days in the phenotyper.
Description: Mutants showed a longer latency to visit the center zone of the arena and showed a trend toward lower percentage of distance moved in the center zone while making a similar number of visits to the center zone as control mice.
Exp Paradigm: NA
Description: Mutant mice showed a tendency to travel a longer distance than control littermates to find a new target hole during the first three reversal trials but did finally acquire/maintain the new strategy, suggesting impaired behavioral flexibility.
Exp Paradigm: The modified barnes maze test is designed to improve assessment of spatial learning by avoiding development of serial strategy. the maze contains 44 holes divided into three rings, instead of 24 holes in one perimeter.
Description: Mutant mice show increased c-fos activity in the prefrontal cortex (pfc), motor cortex (mcx) and somatosensory cortex (sscx) at postnatal days 12 and 19.
Exp Paradigm: NA
Electroencephalogram (eeg): signature of seizure/epilepsy1
Increased
Description: Mutant mice show epileptiform activity represented with spike during the sleep and polyspikes complex during awake state. surviving mutants showed strong epileptiform activity on ecog, much more severe than the other three mouse lines.
Exp Paradigm: NA
Description: Mutant mice showed increased mortality and decreased survival rate. about 50% of the mice did not survive beyond postnatal day 14.
Exp Paradigm: NA
Description: Mutants show decrease in proportion of overall activity duration in the phenotyper during the light phases.
Exp Paradigm: The diurnal rhythm was assessed by monitoring undisturbed behavior in an automated home-cage system (phenotyper) enriched with a shelter for three consecutive days. parameters measured included activity, dark-light ratio, habituation, kinematics, sheltering, and phase transition.
Description: Mutants show increase in proportion of activity duration during the first 3 h of the dark phase in the home-cage environment during the first dark phase. mutants show no change in overall activity during the dark phase. mutants show no change in circadian rhythm assessed by changes in the activity in anticipation of, and response to, day/night transitions and proportion of time spent outside the shelter.
Exp Paradigm: The diurnal rhythm was assessed by monitoring undisturbed behavior in an automated home-cage system (phenotyper) enriched with a shelter for three consecutive days. parameters measured included activity, dark-light ratio, habituation, kinematics, sheltering, and phase transition.
Description: Mutants twitch spontaneously, predominantly during the light or inactive phase of the murine circadian cycle, indicating an epileptic event. mutants jump spontaneously in an apparent sleep or inactive state during the light or inactive phase of the murine circadian cycle, indicating an epileptic event.
Exp Paradigm: A twitch was defined as a sudden, myoclonic jerk of the animals body from resting state (apparent sleep) that did not cause the mouse to wake. jumps were differentiated from twitches by a change in the position of the mouse in the cage and were followed by activity and sometimes accompanied by a straub tail reaction.
Electroencephalogram (eeg): signature of seizure/epilepsy1
Increased
Description: Mutants show automatic spike wave discharges (swds) during 24hr ecog recording. mutant mice showed frequent, high amplitude spike-wave discharges in both hippocampal and cortical recordings that were visually not detected in control mice.
Exp Paradigm: Eeg electrodes were implanted in the hippocampal ca1 region or neocortex.
Description: In the elevated plus maze mutant mice showed delayed latency to enter the open arms, spent less time on the open arms, and visited the open arms less frequently compared to control mice.
Exp Paradigm: NA
Description: In the dark-light box test, mutant mice showed longer latency to visit the bright compartment, spent less time in the bright compartment, and made fewer visits to the bright compartment, compared to control mice.
Exp Paradigm: NA
Description: Mutants spend less time on top of the shelter in the enriched cage compared to controls.
Exp Paradigm: Spontaneous behavior was automatically monitored for 3 days in the phenotyper.
Description: Mutants showed a longer latency to visit the center zone of the arena and showed a trend toward lower percentage of distance moved in the center zone while making a similar number of visits to the center zone as control mice.
Exp Paradigm: NA
Description: Mutant mice showed significantly longer escape latency during the first reversal trial and longer distance travelled to the new target hole.
Exp Paradigm: The modified barnes maze test is designed to improve assessment of spatial learning by avoiding development of serial strategy. the maze contains 44 holes divided into three rings, instead of 24 holes in one perimeter.
Description: Mutants tended to visit more holes in the target octant compared to control mice during the first probe trial. during the second probe trial, mutant mice tended to visit more holes in the old target octant then control littermates. mutants show no differences in the probability of hole visits in the new target octant during the second probe trial. during the third probe trial, performed after three additional reversal trials, no differences in the probability of holes visits were found between mutants and controls
Exp Paradigm: The modified barnes maze test is designed to improve assessment of spatial learning by avoiding development of serial strategy. the maze contains 44 holes divided into three rings, instead of 24 holes in one perimeter.
Description: During reversal learning, mutant mice needed significantly fewer entries to reach the 80% criterion.
Exp Paradigm: Cognitional wall task uses an operant wall with three entry holes placed in the phenotyper cage in front of a reward dispenser. during the first 2 days, mice had to learn to earn food rewards by passing through the left hole (discrimination learning) and during days 3 and 4 the right hole was rewarded (reversal learning).
Description: Mutants showed a mild delay in the learning phase compared to controls. mutants show similar spatial learning curves due to reduction in escape latency and distance moved to reach the target with increasing number of training sessions, as do controls.
Exp Paradigm: The modified barnes maze test is designed to improve assessment of spatial learning by avoiding development of serial strategy. the maze contains 44 holes divided into three rings, instead of 24 holes in one perimeter.
Cued or contextual fear conditioning: active avoidance1
Increased
Description: Mutant mice showed a greater learning effect compared to control mice during all three dark phases and a trend toward lower aversion index over days, compared to controls.
Exp Paradigm: Avoidance learning was studied in an enriched home-cage with a shelter with two entrances, by first assessing the preferred entrance during the first 4 days in the cage of each individual mouse and subsequently applying an aversive stimulus (bright illumination) every time an animal enters the shelter through its preferred entrance. the changes in the preference index (fraction of entries via the preferred entrance) were considered as a measure of cognitive response and the changes in the aversion index (a change in the time spent in now illuminated shelter) as the averseness of the bright illumination.
Description: Mutants showed increased escape latency without training, compared to controls.
Exp Paradigm: The modified barnes maze test is designed to improve assessment of spatial learning by avoiding development of serial strategy. the maze contains 44 holes divided into three rings, instead of 24 holes in one perimeter.
Description: Mutants show decrease in proportion of overall activity duration in the phenotyper during the light phases. the reverse 129sv line mice had lower activity compared to congenic bl6 and stxbp1cre/+ mice.
Exp Paradigm: The diurnal rhythm was assessed by monitoring undisturbed behavior in an automated home-cage system (phenotyper) enriched with a shelter for three consecutive days. parameters measured included activity, dark-light ratio, habituation, kinematics, sheltering, and phase transition.
Description: Mutants show increased activity in response to dark phase. mutants show increase in proportion of activity duration during the first 3 h of the dark phase in the home-cage environment during the first dark phase. mutants show no change in circadian rhythm assessed by changes in the activity in anticipation of, and response to, day/night transitions and proportion of time spent outside the shelter. the reverse 129sv line mice had lower activity compared to congenic bl6 and stxbp1cre/+ mice.
Exp Paradigm: The diurnal rhythm was assessed by monitoring undisturbed behavior in an automated home-cage system (phenotyper) enriched with a shelter for three consecutive days. parameters measured included activity, dark-light ratio, habituation, kinematics, sheltering, and phase transition.
Description: Mutants jump spontaneously in an apparent sleep or inactive state during the light or inactive phase of the murine circadian cycle, indicating an epileptic event.
Exp Paradigm: Jumps were differentiated from twitches by a change in the position of the mouse in the cage and were followed by activity and sometimes accompanied by a straub tail reaction.
Description: Mutants twitch spontaneously, predominantly during the light or inactive phase of the murine circadian cycle, indicating an epileptic event.
Exp Paradigm: A twitch was defined as a sudden, myoclonic jerk of the animals body from resting state (apparent sleep) that did not cause the mouse to wake.
Description: Mutants fail to consume the reward cracker in the novelty-induced hypophagia test.
Exp Paradigm: Novelty induced hypophagia was tested: measuring time to eat the cracker in the new cage.
Description: Mutants show increased latency to enter the open arms, decreased time spent on the open arms, and decreased numbers of open arm visits compared to controls. mutants and wild type mice showed profound anxiety-like behavior on the epm in comparison to conditional and congenic b6 mice.
Exp Paradigm: NA
