PDF(Pubmed)
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/).
摘要：
SLC6A1基因中的遗传变异可通过改变蛋白质功能而引起广泛的表型疾病谱。因此，需要对临床相关的基因型-表型关联进行系统策划,以了解疾病机制并改善治疗决策。我们汇总了172名可能具有致病性/致病性（lp/p）SLC6A1变体的个体的遗传和临床数据，以及184个变体（14.1%lp/p）的功能数据。临床和功能数据可用于126个个体的子集。我们探索了GAT13D结构上变异位置与变异致病性的潜在关联，改变了分子功能，和使用生物信息学方法的表型严重性。针对患者富集GAT1跨膜结构域1、6和细胞外环4(EL4)超过群体变体。在功能测试的错义变体(n=156)中，与配体的空间接近度与GAT1转运蛋白活性的功能丧失有关.对于完全丧失体外GABA摄取的变体，我们发现患有严重疾病的患者与患有严重疾病的患者相比增加了4.6倍非严重疾病（P=2.9e-3，95%CI：1.5-15.3）。总之,我们描绘了3D结构和变异致病性之间的关联，变体函数，和SLC6A1相关疾病的表型。这些知识支持对GAT1功能的生物学知情变体解释和研究。我们所有的数据都可以在SLC6A1门户（https://slc6a1-portal）中进行交互探索。broadinstitute.org/)。
