Transcriptome analysis of neural progenitor cells derived from Lowe Syndrome induced pluripotent stem cells

Lowe Syndrome (LS) is caused by loss-of-function mutations in the X-linked gene OCRL that codes for a 901 amino acid protein, inositol polyphosphate 5-phosphatase, which plays a key role in endosome recycling, clathrin coated pit formation and actin polymerization. It is characterized by congenital cataracts, intellectual and developmental disability, and renal proximal tubular dysfunction. Patients are also at high risk for developing glaucoma and seizures. We recently developed induced pluripotent stem cells (iPSCs) from three patients with LS who have hypomorphic variants affected the 3’ end of the gene, and their neurotypical brothers to serve as controls. In this study, we used RNA sequencing (RNA-seq) to obtain a transcriptome profile in neural progenitor cells (NPCs). Thirty-six differentially expressed genes (DEGs) were found in patient/control comparisons that were shared across all three sets of sibling pairs. Interestingly, two-thirds of these genes have previously been found to be involved in neuropsychiatric and neurodevelopmental disorders. Furthermore, 14 of the DEGs are strong candidate genes for a variety of eye disorders, including glaucoma development. The most notable example is EFEMP1, which was significantly increased in LS NPCs. These DEGs found in NPCs could reflect similar alterations occurring in eye tissues or their progenitor cells from LS. Overall, the RNA-seq findings present several molecular pathways that could explain the underlying basis for the neurodevelopmental and eye problems seen in boys with LS.

Lowe综合征（Lowe Syndrome, LS）是由X连锁基因OCRL的功能丧失性突变引发的，该基因编码含901个氨基酸的肌醇多磷酸5-磷酸酶（inositol polyphosphate 5-phosphatase），此酶在内体循环、网格蛋白包被小窝形成及肌动蛋白聚合过程中发挥关键调控作用。该病以先天性白内障、智力与发育障碍以及肾近端小管功能异常为核心临床特征，患者同时罹患青光眼和癫痫的风险显著升高。我们近期从3例携带影响基因3'端的低功能变异的Lowe综合征患者，及其神经表型正常的同胞兄弟（作为对照）中诱导生成了诱导多能干细胞（induced pluripotent stem cells, iPSCs）。本研究通过RNA测序（RNA-seq）获取了神经前体细胞（neural progenitor cells, NPCs）的转录组谱；在患者与对照的比较分析中，共筛选得到36个在全部三对同胞对中均存在差异表达的基因（differentially expressed genes, DEGs）。值得注意的是，其中三分之二的基因此前已被证实与神经精神疾病及神经发育障碍密切相关。此外，14个差异表达基因是包括青光眼在内的多种眼部疾病的强候选致病基因，其中最受关注的是EFEMP1，其在Lowe综合征神经前体细胞中的表达水平显著上调。上述在神经前体细胞中发现的差异表达基因，或可反映Lowe综合征患者眼部组织或其祖细胞内发生的类似分子改变。总体而言，本研究的RNA测序结果揭示了多条潜在分子通路，可为阐释男性Lowe综合征患者所出现的神经发育与眼部病变的分子机制提供重要依据。