Dataset Information

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

ABSTRACT: 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 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/).

SUBMITTER: Stefanski A

PROVIDER: S-EPMC10689929 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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

Stefanski Arthur A Pérez-Palma Eduardo E Brünger Tobias T Montanucci Ludovica L Gati Cornelius C Klöckner Chiara C Johannesen Katrine M KM Goodspeed Kimberly K Macnee Marie M Deng Alexander T AT Aledo-Serrano Ángel Á Borovikov Artem A Kava Maina M Bouman Arjan M AM Hajianpour M J MJ Pal Deb K DK Engelen Marc M Hagebeuk Eveline E O EEO Shinawi Marwan M Heidlebaugh Alexis R AR Oetjens Kathryn K Hoffman Trevor L TL Striano Pasquale P Freed Amanda S AS Futtrup Line L Balslev Thomas T Abulí Anna A Danvoye Leslie L Lederer Damien D Balci Tugce T Nouri Maryam Nabavi MN Butler Elizabeth E Drewes Sarah S van Engelen Kalene K Howell Katherine B KB Khoury Jean J May Patrick P Trinidad Marena M Froelich Steven S Lemke Johannes R JR Tiller Jacob J Freed Amber N AN Kang Jing-Qiong JQ Wuster Arthur A Møller Rikke S RS Lal Dennis D

Brain : a journal of neurology 20231201 12

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 fo ...[more]

PMID: 37647852

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Project description:Solute carrier family 6 member 1 (SLC6A1) is abundantly expressed in the developing brain even before the CNS is formed. Its encoded GABA transporter 1 (GAT-1) is responsible for the reuptake of GABA into presynaptic neurons and glia, thereby modulating neurotransmission. GAT-1 is expressed globally in the brain, in both astrocytes and neurons. The GABA uptake function of GAT-1 in neurons cannot be compensated for by other GABA transporters, while the function in glia can be partially replaced by GABA transporter 3. Recently, many variants in SLC6A1 have been associated with a spectrum of epilepsy syndromes and neurodevelopmental disorders, including myoclonic atonic epilepsy, childhood absence epilepsy, autism, and intellectual disability, but the pathomechanisms associated with these phenotypes remain unclear. The presence of GAT-1 in both neurons and astrocytes further obscures the role of abnormal GAT-1 in the heterogeneous disease phenotype manifestations. Here we examine the impact on transporter trafficking and function of 22 SLC6A1 variants identified in patients with a broad spectrum of phenotypes. We also evaluate changes in protein expression and subcellular localization of the variant GAT-1 in various cell types, including neurons and astrocytes derived from human patient induced pluripotent stem cells. We found that a partial or complete loss-of-function represents a common disease mechanism, although the extent of GABA uptake reduction is variable. The reduced GABA uptake appears to be due to reduced cell surface expression of the variant transporter caused by variant protein misfolding, endoplasmic reticulum retention, and subsequent degradation. Although the extent of reduction of the total protein, surface protein, and the GABA uptake level of the variant transporters is variable, the loss of GABA uptake function and endoplasmic reticulum retention is consistent across induced pluripotent stem cell-derived cell types, including astrocytes and neurons, for the surveyed variants. Interestingly, we did not find a clear correlation of GABA uptake function and the disease phenotypes, such as myoclonic atonic epilepsy versus developmental delay, in this study. Together, our study suggests that impaired transporter protein trafficking and surface expression are the major disease-associated mechanisms associated with pathogenic SLC6A1 variants. Our results resemble findings from pathogenic variants in other genes affecting the GABA pathway, such as GABAA receptors. This study provides critical insight into therapeutic developments for SLC6A1 variant-mediated disorders and implicates that boosting transporter function by either genetic or pharmacological approaches would be beneficial.

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Dataset Information

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

Publications

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

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