Article (Scientific journals)
SLC6A1 variant pathogenicity, molecular function, and phenotype: a genetic and clinical analysis
Stefanski, Arthur; Pérez-Palma, Eduardo; Brünger, Tobias et al.
2023In Brain: a Journal of Neurology, p. 292
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Keywords :
Epilepsy; SLC6A1; autism; Neurodevelopment
Abstract :
[en] Genetic 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 vs. non-severe disease (P = 2.9e-3, 95% CI: 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 (
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Stefanski, Arthur
Pérez-Palma, Eduardo
Brünger, Tobias
Montanucci, Ludovica
Gati, Cornelius
Klöckner, Chiara
Johannesen, Katrine M.
Goodspeed, Kimberly
Macnee, Marie
Deng, Alexander T.
Aledo-Serrano, Ángel
Borovikov, Artem
Kava, Maina
Bouman, Arjan M.
Hajianpour, M. J.
Pal, Deb K.
Engelen, Marc
Hagebeuk, Eveline E. O.
Shinawi, Marwan
Heidlebaugh, Alexis R.
Oetjens, Kathryn
Hoffman, Trevor L.
Striano, Pasquale
Freed, Amanda S.
Futtrup, Line
Balslev, Thomas
Abulí, Anna
Danvoye, Leslie
Lederer, Damien
Balci, Tugce
Nabavi Nouri, Maryam
Butler, Elizabeth
Drewes, Sarah
van Engelen, Kalene
Howell, Katherine B.
Khoury, Jean
May, Patrick  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Trinidad, Marena
Froelich, Steven
Lemke, Johannes R.
Tiller, Jacob
Freed, Amber N.
Kang, Jing-Qiong
Wuster, Arthur
Møller, Rikke S.
Lal, Dennis
More authors (36 more) Less
External co-authors :
Language :
Title :
SLC6A1 variant pathogenicity, molecular function, and phenotype: a genetic and clinical analysis
Publication date :
30 August 2023
Journal title :
Brain: a Journal of Neurology
Publisher :
Oxford University Press, Oxford, United Kingdom
Pages :
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
FnR Project :
FNR16394868 - Epileptogenesis Of Genetic Epilepsies, 2021 (01/10/2021-...) - Alexander Skupin
Name of the research project :
Treat-ION, FOR2715
Funders :
FNR - Fonds National de la Recherche [LU]
Available on ORBilu :
since 31 August 2023


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