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

Area of Science:

• Genetics
• Neuroscience
• Structural Biology

Background:

• Genetic variants in the SLC6A1 gene are associated with a wide range of phenotypes due to altered protein function.
• Understanding genotype-phenotype correlations is crucial for elucidating disease mechanisms and guiding therapeutic strategies for SLC6A1-related disorders.

Purpose of the Study:

• To systematically curate and analyze genotype-phenotype and functional data for SLC6A1 variants.
• To explore the relationship between variant positions on the GAT1 3D structure, variant pathogenicity, molecular function, and clinical phenotype severity.

Main Methods:

• Aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants.
• Utilized bioinformatic approaches to analyze variant associations with the GAT1 3D structure, including transmembrane domains and extracellular loops.
• Assessed in vitro GAT1 transporter activity for functional variant characterization.

Main Results:

• Specific GAT1 structural regions (transmembrane domains 1, 6, and extracellular loop 4) were enriched for patient variants.
• Spatial proximity of missense variants to the ligand binding site correlated with loss-of-function in GAT1 transporter activity.
• Variants causing complete loss of in vitro GABA uptake showed a significant enrichment in patients with severe disease phenotypes.

Conclusions:

• Established associations between 3D GAT1 structure, variant pathogenicity, functional impact, and phenotype severity in SLC6A1-related disorders.
• The findings support biology-informed variant interpretation and advance research into GAT1 transporter function.
• An interactive SLC6A1 portal is available for data exploration.