Open AccessProtein structure and phenotypic analysis of pathogenic and population missense variants in STXBP 1
Author(s) -
Suri Mohnish,
Evers Jochem M. G.,
Laskowski Roman A.,
O'Brien Sinead,
Baker Kate,
ClaytonSmith Jill,
Dabir Tabib,
Josifova Dragana,
Joss Shelagh,
Kerr Bronwyn,
Kraus Alison,
McEntagart Meriel,
Morton Jenny,
Smith Audrey,
Splitt Miranda,
Thornton Janet M.,
Wright Caroline F.
Publication year - 2017
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.304
Subject(s) - missense mutation , genetics , phenotype , biology , population , exome sequencing , loss function , haploinsufficiency , exome , gene , medicine , environmental health
Background Syntaxin‐binding protein 1, encoded by STXBP 1 , is highly expressed in the brain and involved in fusing synaptic vesicles with the plasma membrane. Studies have shown that pathogenic loss‐of‐function variants in this gene result in various types of epilepsies, mostly beginning early in life. We were interested to model pathogenic missense variants on the protein structure to investigate the mechanism of pathogenicity and genotype–phenotype correlations. Methods We report 11 patients with pathogenic de novo mutations in STXBP 1 identified in the first 4293 trios of the Deciphering Developmental Disorder ( DDD ) study, including six missense variants. We analyzed the structural locations of the pathogenic missense variants from this study and the literature, as well as population missense variants extracted from Exome Aggregation Consortium (Ex AC ). Results Pathogenic variants are significantly more likely to occur at highly conserved locations than population variants, and be buried inside the protein domain. Pathogenic mutations are also more likely to destabilize the domain structure compared with population variants, increasing the proportion of (partially) unfolded domains that are prone to aggregation or degradation. We were unable to detect any genotype–phenotype correlation, but unlike previously reported cases, most of the DDD patients with STXBP 1 pathogenic variants did not present with very early‐onset or severe epilepsy and encephalopathy, though all have developmental delay with intellectual disability and most display behavioral problems and suffered seizures in later childhood. Conclusion Variants across STXBP 1 that cause loss of function can result in severe intellectual disability with or without seizures, consistent with a haploinsufficiency mechanism. Pathogenic missense mutations act through destabilization of the protein domain, making it prone to aggregation or degradation. The presence or absence of early seizures may reflect ascertainment bias in the literature as well as the broad recruitment strategy of the DDD study.