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.
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
Phenotypic and genetic analysis of children with unexplained neurodevelopmental delay and neurodevelopmental comorbidities in a Chinese cohort using trio-based whole-exome sequencing
Clinical whole exome sequencing revealed de novo heterozygous stop-gain and missense variants in the STXBP1 gene associated with epilepsy in Saudi families
Rescue Type:
RESCUE-Pharmaceutical
Rescue Paradigm:
Congenic C57BL/6J Stxbp1 heterozygous mice were treated with the antiepileptic drug, levetiracetam. One day after saline injection, mice were injected with levetiracetam (50 mg/kg, i.p.) and treatment continued once daily for 5 days.
Treatment does not improve measured phenotype (was expected to do so)
Ameliorated
Treatment provides partial correction or improvement of measured phenotype
No adverse effect
Treatment does not affect the parameter adversely
Sustained effect
Treatment has long term effect of restoration or amelioration, tested AFTER stopping administration (not applied for continuing long-term treatment) . Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
No sustained effect
Treatment has no long term of restoration or amelioration detectable, after stopping administration. Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
Electroencephalogram (eeg): signature of seizure/epilepsy1
Ameliorated
Description: Mutants treated with five doses of levetiracetam showed reduced spike wave discharges but not to control levels.
Exp Paradigm: Eeg electrodes were implanted in the hippocampal ca1 region or neocortex.
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 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.
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: 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.
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: 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: 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.
