Department of Molecular Medicine, IRCCS Stella Maris Foundation, Pisa, Italy.
Department of Biology, University of Pisa, Pisa, Italy.
Ann Clin Transl Neurol. 2020 Apr;7(4):584-589. doi: 10.1002/acn3.51018. Epub 2020 Mar 25.
Autosomal recessive spastic paraplegia 52 is caused by biallelic mutations in AP4S1 which encodes a subunit of the adaptor protein complex 4 (AP-4). Using next-generation sequencing, we identified three novel unrelated SPG52 patients from a cohort of patients with cerebral palsy. The discovered variants in AP4S1 lead to reduced AP-4 complex formation in patient-derived fibroblasts. To further understand the role of AP4S1 in neuronal development and homeostasis, we engineered the first zebrafish model of AP-4 deficiency using morpholino-mediated knockdown of ap4s1. In this model, we discovered several phenotypes mimicking SPG52, including altered CNS development, locomotor deficits, and abnormal neuronal excitability.
常染色体隐性痉挛性截瘫 52 是由编码衔接蛋白复合物 4（AP-4）亚基的 AP4S1 双等位基因突变引起的。使用下一代测序技术，我们从脑瘫患者队列中鉴定出三个新的无关联的 SPG52 患者。在患者来源的成纤维细胞中，发现的 AP4S1 中的变异导致 AP-4 复合物形成减少。为了进一步了解 AP4S1 在神经元发育和稳态中的作用，我们使用 morpholino 介导的 ap4s1 敲低构建了第一个 AP-4 缺乏的斑马鱼模型。在这个模型中，我们发现了几个类似于 SPG52 的表型，包括中枢神经系统发育异常、运动缺陷和神经元兴奋性异常。
