Publication:
SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis

Simple item page
dc.contributor.authorStefanski, Arthur
dc.contributor.authorPérez Palma, Eduardo
dc.contributor.authorBrünger, Tobias
dc.contributor.authorMontanucci, Ludovica
dc.contributor.authorGati, Cornelius
dc.contributor.authorKlöckner, Chiara
dc.contributor.authorJohannesen, Katrine
dc.contributor.authorGoodspeed, Kimberly
dc.contributor.authorMacnee, Marie
dc.contributor.authorDeng, Alexander
dc.contributor.authorAledo, Ángel
dc.contributor.authorBorovikov,Artem
dc.contributor.authorKava, Maina
dc.contributor.authorBouman, Arjan
dc.contributor.authorHajianpour, M.
dc.contributor.authorPal, Deb
dc.contributor.authorEngelen, Marc
dc.contributor.authorHagebeuk, Eveline
dc.contributor.authorShinawi, Marwan
dc.contributor.authorHeidlebaugh, Alexis
dc.contributor.authorOetjens, Kathryn
dc.contributor.authorHoffman, Trevor
dc.contributor.authorStriano, Pasquale
dc.contributor.authorFreed, Amanda
dc.contributor.authorFuttrup, Line
dc.contributor.authorBalslev, Thomas
dc.contributor.authorAbulí, Anna
dc.contributor.authorDanvoye, Leslie
dc.contributor.authorLederer, Damien
dc.contributor.authorBalci, Tugce
dc.contributor.authorNabavi, Maryam
dc.contributor.authorButler, Elizabeth
dc.contributor.authorDrewes, Sarah
dc.contributor.authorVan Engelen, Kalene
dc.contributor.authorHowell, Katherine
dc.contributor.authorKhoury, Jean
dc.contributor.authorMay, Patrick
dc.contributor.authorTrinidad, Marena
dc.contributor.authorFroelich, Steven
dc.contributor.authorLemke, Johannes
dc.date.accessioned2024-06-03T20:45:25Z
dc.date.available2024-06-03T20:45:25Z
dc.date.issued2023
dc.descriptionTiller, Jacob; Freed, Amber; Kang, Jing-Qiong; Wuster, Arthur; Møller, Rikke; Lal, Dennis.
dc.description.abstractGenetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10-3, 95% confidence interval: 1.5-15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/).
dc.description.versionAceptada
dc.identifier.citationStefanski A, Pérez-Palma E, Brünger T, Montanucci L, Gati C, Klöckner C, Johannesen KM, Goodspeed K, Macnee M, Deng AT, Aledo-Serrano Á, Borovikov A, Kava M, Bouman AM, Hajianpour MJ, Pal DK, Engelen M, Hagebeuk EEO, Shinawi M, Heidlebaugh AR, Oetjens K, Hoffman TL, Striano P, Freed AS, Futtrup L, Balslev T, Abulí A, Danvoye L, Lederer D, Balci T, Nouri MN, Butler E, Drewes S, van Engelen K, Howell KB, Khoury J, May P, Trinidad M, Froelich S, Lemke JR, Tiller J, Freed AN, Kang JQ, Wuster A, Møller RS, Lal D. SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis. Brain. 2023 Dec 1;146(12):5198-5208. doi: 10.1093/brain/awad292
dc.identifier.doihttps://doi.org/10.1093/brain/awad292
dc.identifier.urihttps://hdl.handle.net/11447/9003
dc.language.isoen
dc.subjectSLC6A1
dc.subjectAutism
dc.subjectEpilepsy
dc.subjectGenetics
dc.subjectNeurodevelopmental disorder
dc.titleSLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis
dc.typeArticle
dcterms.accessRightsAcceso Abierto
dcterms.sourceBrain : a journal of neurology
dspace.entity.typePublication
relation.isAuthorOfPublication31623ebd-7791-4ceb-b04c-c69d7496b40f
relation.isAuthorOfPublication.latestForDiscovery31623ebd-7791-4ceb-b04c-c69d7496b40f

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
SLC6A1 variant pathogenicity, molecular function and phenotype a genetic and clinical analysis.pdf
Size:
573.56 KB
Format:
Adobe Portable Document Format
Description:
Texto Completo
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
347 B
Format:
Item-specific license agreed upon to submission
Description:
Download

Collections

Artículos Medicina y Ciencias de la Salud

Implementado por OpenGeek Services