Protein structure and phenotypic analysis of pathogenic and population missense variants in STXBP1 .

Autor: Suri M; Nottingham Regional Genetics ServiceNottingham University Hospitals NHS TrustCity Hospital Campus, The Gables, Hucknall RoadNottinghamNG5 1PBUK., Evers JMG; European Bioinformatics Institute (EMBL-EBI)Wellcome Genome Campus, HinxtonCambridgeCB10 1SDUK., Laskowski RA; European Bioinformatics Institute (EMBL-EBI)Wellcome Genome Campus, HinxtonCambridgeCB10 1SDUK., O'Brien S; MRC Cognition and Brain Sciences Unit15 Chaucer RoadCambridgeCB2 7EFUK., Baker K; MRC Cognition and Brain Sciences Unit15 Chaucer RoadCambridgeCB2 7EFUK.; Department of Medical GeneticsUniversity of CambridgeCambridge Biomedical CampusCambridgeCB2 0QQUK., Clayton-Smith J; Manchester Centre for Genomic MedicineSt Mary's Hospital, Central Manchester University Hospitals NHS Foundation TrustManchester Academic Health Science CentreManchesterM13 9WLUK., Dabir T; Northern Ireland Regional Genetics CentreBelfast Health and Social Care TrustBelfast City HospitalLisburn RoadBelfastBT9 7ABUK., Josifova D; South East Thames Regional Genetics CentreGuy's and St Thomas' NHS Foundation TrustGuy's HospitalGreat Maze PondLondonSE1 9RTUK., Joss S; West of Scotland Genetics ServiceQueen Elizabeth University HospitalLaboratory Medicine BuildingGlasgowG51 4TFUK., Kerr B; Manchester Centre for Genomic MedicineSt Mary's Hospital, Central Manchester University Hospitals NHS Foundation TrustManchester Academic Health Science CentreManchesterM13 9WLUK., Kraus A; Yorkshire Regional Genetics ServiceDepartment of Clinical GeneticsLeeds Teaching Hospitals NHS TrustChapel Allerton HospitalChapeltown RoadLeedsLS7 4SAUK., McEntagart M; South West Thames Regional Genetics CentreSt George's Healthcare NHS TrustSt George's University of LondonCranmer TerraceLondonSW17 0REUK., Morton J; West Midlands Regional Clinical Genetics Service and Birmingham Health PartnersBirmingham Women's and Children's NHS Foundation TrustBirmingham Women's HospitalMindelsohn Way, EdgbastonBirminghamB15 2TGUK., Smith A; Yorkshire Regional Genetics ServiceDepartment of Clinical GeneticsLeeds Teaching Hospitals NHS TrustChapel Allerton HospitalChapeltown RoadLeedsLS7 4SAUK., Splitt M; Northern Genetics ServiceNewcastle upon Tyne Hospitals NHS Foundation TrustInstitute of Human GeneticsInternational Centre for LifeCentral ParkwayNewcastle upon TyneNE1 3BZUK., Thornton JM; European Bioinformatics Institute (EMBL-EBI)Wellcome Genome Campus, HinxtonCambridgeCB10 1SDUK., Wright CF; Wellcome Trust Sanger InstituteWellcome Genome Campus, HinxtonCambridgeCB1 8RQUK.; University of Exeter Medical SchoolRoyal Devon & Exeter HospitalBarrack RoadExeterEX2 5DWUK.
Jazyk: angličtina
Zdroj: Molecular genetics & genomic medicine [Mol Genet Genomic Med] 2017 Jun 20; Vol. 5 (5), pp. 495-507. Date of Electronic Publication: 2017 Jun 20 (Print Publication: 2017).
DOI: 10.1002/mgg3.304
Abstrakt: Background: Syntaxin-binding protein 1, encoded by STXBP1 , 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 STXBP1 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 (ExAC).
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 STXBP1 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 STXBP1 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.
Databáze: MEDLINE
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