Department of Biochemistry and Molecular Genetics, American university of Beirut, Beirut, Lebanon.
Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Transl Psychiatry. 2023 Dec 21;13(1):404. doi: 10.1038/s41398-023-02702-0.
The landscape of autism spectrum disorder (ASD) in Lebanon is unique because of high rates of consanguinity, shared ancestry, and increased remote consanguinity. ASD prevalence in Lebanon is 1 in 68 with a male-to-female ratio of 2:1. This study aims to investigate the impact of an inherited deletion in UBLCP1 (Ubiquitin-Like Domain-Containing CTD Phosphatase 1) on the ubiquitin-proteasome system (UPS) and proteolysis. Whole exome sequencing in a Lebanese family with ASD without pathogenic copy number variations (CNVs) uncovered a deletion in UBLCP1. Functional evaluation of the identified variant is described in fibroblasts from the affected. The deletion in UBLCP1 exon 10 (g.158,710,261CAAAG > C) generates a premature stop codon interrupting the phosphatase domain and is predicted as pathogenic. It is absent from databases of normal variation worldwide and in Lebanon. Wild-type UBLCP1 is widely expressed in mouse brains. The mutation results in decreased UBLCP1 protein expression in patient-derived fibroblasts from the autistic patient compared to controls. The truncated UBLCP1 protein results in increased proteasome activity decreased ubiquitinated protein levels, and downregulation in expression of other proteasome subunits in samples from the affected compared to controls. Inhibition of the proteasome by using MG132 in proband cells reverses alterations in gene expression due to the restoration of protein levels of the common transcription factor, NRF1. Finally, treatment with gentamicin, which promotes premature termination codon read-through, restores UBLCP1 expression and function. Discovery of an ASD-linked mutation in UBLCP1 leading to overactivation of cell proteolysis is reported. This, in turn, leads to dysregulation of proteasome subunit transcript levels as a compensatory response.
自闭症谱系障碍（ASD）在黎巴嫩的发病情况较为独特，这主要是因为其存在较高的近亲结婚率、共同的祖先和远距离近亲结婚率。黎巴嫩的 ASD 患病率为 1/68，男女比例为 2:1。本研究旨在探究 UBLCP1（泛素样结构域 CTD 磷酸酶 1）基因遗传缺失对泛素蛋白酶体系统（UPS）和蛋白水解的影响。对一个没有致病性拷贝数变异（CNVs）的黎巴嫩 ASD 家系进行外显子组测序，发现 UBLCP1 中存在缺失。对受影响个体的成纤维细胞中鉴定出的变体进行了功能评估。UBLCP1 第 10 外显子（g.158,710,261CAAAG > C）缺失产生一个提前终止密码子，中断了磷酸酶结构域，被预测为致病性。该缺失在全世界和黎巴嫩的正常变异数据库中均不存在。野生型 UBLCP1 在小鼠大脑中广泛表达。与对照相比，突变导致患者来源的成纤维细胞中 UBLCP1 蛋白表达减少。截短的 UBLCP1 蛋白导致蛋白酶体活性增加、泛素化蛋白水平降低以及受影响个体样本中的其他蛋白酶体亚基表达下调。在受影响个体的细胞中使用 MG132 抑制蛋白酶体，通过恢复常见转录因子 NRF1 的蛋白水平，可逆转由于蛋白水平降低导致的基因表达改变。最后，使用庆大霉素（一种促进提前终止密码子通读的药物）治疗可恢复 UBLCP1 的表达和功能。本研究报道了与 ASD 相关的 UBLCP1 基因突变导致细胞蛋白水解过度激活，进而导致蛋白酶体亚基转录水平失调的情况。
