Heterozygous variants in , encoding the GAT-1 GABA transporter, are associated with seizures, developmental delay, and autism. The majority of affected individuals carry missense variants, many of which are recurrent germline mutations, raising the possibility of gain-of-function or dominant-negative effects. To understand the functional consequences, we performed an GABA uptake assay for 213 unique variants, including 24 control variants. variants consistently resulted in a decrease in GABA uptake, in keeping with haploinsufficiency underlying all neurodevelopmental phenotypes. Where present, ClinVar pathogenicity reports correlated well with GABA uptake data; the functional data can inform future reports for the remaining 72% of unscored variants. Surface localization was assessed for 86 variants; two-thirds of loss-of-function missense variants prevented GAT-1 from being present on the membrane while GAT-1 was on the surface but with reduced activity for the remaining third. Surprisingly, recurrent missense variants showed moderate loss-of-function effects that reduced GABA uptake with no evidence for dominant-negative or gain-of-function effects. Using linear regression across multiple missense severity scores to extrapolate the functional data to all potential missense variants, we observe an abundance of GAT-1 residues that are sensitive to substitution. The extent of this missense vulnerability accounts for the clinically observed missense enrichment; overlap with hypermutable CpG sites accounts for the recurrent missense variants. Strategies to increase the expression of the wild-type allele are likely to be beneficial across neurodevelopmental disorders, though the developmental stage and extent of required rescue remain unknown.

中文翻译：

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单倍体不足是 SLC6A1 变异神经发育后果的基础


编码 GAT-1 GABA 转运蛋白的 杂合变异与癫痫、发育迟缓和自闭症有关。大多数受影响的个体携带错义变异，其中许多是反复发生的种系突变，增加了功能获得或显性失活效应的可能性。为了了解其功能后果，我们对 213 个独特变体（包括 24 个对照变体）进行了 GABA 摄取测定。变异始终导致 GABA 摄取减少，与所有神经发育表型背后的单倍体不足保持一致。如果存在，ClinVar 致病性报告与 GABA 摄取数据密切相关；功能数据可以为未来报告剩余 72% 的未评分变体提供信息。评估了 86 种变体的表面定位；三分之二的功能丧失错义变体阻止 GAT-1 出现在膜上，而 GAT-1 位于表面，但其余三分之一的活性降低。令人惊讶的是，反复出现的错义变异表现出中度的功能丧失效应，减少了 GABA 的摄取，但没有证据表明显性失活或功能获得效应。使用跨多个错义严重性评分的线性回归将功能数据外推到所有潜在的错义变体，我们观察到大量对取代敏感的 GAT-1 残基。这种错义脆弱性的程度解释了临床观察到的错义富集；与超可变 CpG 位点的重叠导致了反复发生的错义变异。尽管发育阶段和所需救援的程度仍然未知，但增加野生型等位基因表达的策略可能对神经发育障碍有益。