Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Myelin Disorders Clinic, Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran.
Ann Hum Genet. 2020 Jul;84(4):315-323. doi: 10.1111/ahg.12378. Epub 2020 Feb 20.
The human dopamine transporter (hDAT) participates in dopamine homeostasis by clearing dopamine from the extracellular space using secondary active transport. Dysregulation of hDAT has been reported to be associated with different neuropsychiatric disorders. Dopamine transporter deficiency syndrome (DTDS) is a complex disease caused by defects in dopamine uptake within the synaptic cleft and patients manifest parkinsonian features. The extracellular loops are crucial for DAT activity and defects in these regions disturb dopamine transport. In the present study, a 3.5-year-old female in a consanguineous Iranian family with an initial diagnosis of gait imbalance and speech delay has been identified. We utilized whole-exome sequencing (WES) to identify the possible genetic defect(s). WES identified a novel homozygous in-frame indel variant, c.1139_1150del; p.(Gly380_Lys384delinsGlu), in the SLC6A3 gene (NM_001044.4), as the most likely disease-susceptibility variant. This variant is located in extracellular loop 4 (EL4) of the DAT protein. Our study highlights the role of extracellular loops and shows the EL4 of hDAT as a critical region for the protein activity. The identified variant in the EL4 region of DAT is predicted to compromise DAT function and may lead to DTDS in this case. However, complementary studies are required to confirm.
人类多巴胺转运体（hDAT）通过次级主动转运从细胞外间隙清除多巴胺，参与多巴胺的动态平衡。hDAT 的失调与多种神经精神疾病有关。多巴胺转运体缺陷综合征（DTDS）是一种复杂的疾病，由突触间隙内多巴胺摄取缺陷引起，患者表现出帕金森病特征。细胞外环对于 DAT 的活性至关重要，这些区域的缺陷会干扰多巴胺的转运。在本研究中，我们鉴定了一名来自伊朗有血缘关系家庭的 3.5 岁女性，她最初被诊断为步态失衡和言语迟缓。我们利用全外显子组测序（WES）来鉴定可能的遗传缺陷。WES 发现了 SLC6A3 基因（NM_001044.4）中一个新的纯合框内缺失突变 c.1139_1150del;p.(Gly380_Lys384delinsGlu)，这是最有可能导致疾病的变异。该变异位于 DAT 蛋白的细胞外环 4（EL4）中。我们的研究强调了细胞外环的作用，并表明 hDAT 的 EL4 是蛋白质活性的关键区域。在 DAT 的 EL4 区域中鉴定出的变异预计会损害 DAT 的功能，并可能导致该病例中的 DTDS。然而，需要进一步的互补研究来证实。
