<i>SLC6A1</i> variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis
Journal
Brain
ISSN
0006-8950
1460-2156
Date Issued
2023
Author(s)
Arthur Stefanski
Eduardo Pérez-Palma
Tobias Brünger
Ludovica Montanucci
Cornelius Gati
Chiara Klöckner
Katrine M Johannesen
Kimberly Goodspeed
Marie Macnee
Alexander T Deng
Ángel Aledo-Serrano
Artem Borovikov
Maina Kava
Arjan M Bouman
M J Hajianpour
Deb K Pal
Marc Engelen
Eveline E O Hagebeuk
Marwan Shinawi
Alexis R Heidlebaugh
Kathryn Oetjens
Trevor L Hoffman
Pasquale Striano
Amanda S Freed
Line Futtrup
Thomas Balslev
Anna Abulí
Leslie Danvoye
Damien Lederer
Tugce Balci
Maryam Nabavi Nouri
Elizabeth Butler
Sarah Drewes
Kalene van Engelen
Katherine B Howell
Jean Khoury
Patrick May
Marena Trinidad
Steven Froelich
Johannes R Lemke
Jacob Tiller
Amber N Freed
Jing-Qiong Kang
Arthur Wuster
Rikke S Møller
Dennis Lal
Type
Resource Types::text::journal::journal article
URL Institutional Repository
Abstract
<jats:title>Abstract</jats:title>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>
<jats:p>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).</jats:p>
<jats:p>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/).</jats:p>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>
<jats:p>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).</jats:p>
<jats:p>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/).</jats:p>
Cite this document
Stefanski, A., Pérez-Palma, E., Brünger, T., Montanucci, L., Gati, C., Klöckner, C., Johannesen, K. M., Goodspeed, K., Macnee, M., Deng, A. T., Aledo-Serrano, Á., Borovikov, A., Kava, M., Bouman, A. M., Hajianpour, M. J., Pal, D. K., Engelen, M., Hagebeuk, E. E. O., Shinawi, M., … Lal, D. (2023). slc6a1 variant pathogenicity, molecular function and phenotype: A genetic and clinical analysis. Brain, 146(12), 5198-5208. https://doi.org/10.1093/brain/awad292
Subjects
autism
;
epilepsy
;
genetics
;
neurodevelopmental disorder
;
slc6a1
;
gaba plasma membrane transport proteins
;
genetic association studies
;
humans
;
mutation, missense
;
phenotype
;
virulence
;
beta lactamase
;
gaba transporter 1
;
4 aminobutyric acid carrier
;
slc6a1 protein, human
;
4 aminobutyric acid uptake
;
absence epilepsy
;
article
;
atonic seizure
;
childhood absence epilepsy
;
cohort analysis
;
controlled study
;
crispr-cas9 system
;
developmental delay
;
developmental disorder
;
disease severity
;
epilepsy
;
focal epilepsy
;
gene frequency
;
generalized epilepsy
;
genetic variability
;
genotype
;
hek293t cell line
;
human
;
in vitro study
;
intellectual impairment
;
learning disorder
;
lennox gastaut syndrome
;
loss of function mutation
;
major clinical study
;
mass spectrometry
;
myoclonus seizure
;
pathogenicity
;
phenotype
;
protein structure
;
refractory epilepsy
;
scintillation counting
;
temporal lobe epilepsy
;
whole exome sequencing
;
genetic association study
;
genetics
;
metabolism
;
missense mutation
;
phenotype
;
virulence