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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE129310 | GEO | 2020/05/21

REPOSITORIES: GEO

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Project description:Glaucoma is a neurodegenerative disease in which vision is lost as a result of the apoptosis of retinal ganglion cells. When the trabecular meshwork cells, that regulate aqueous humor outflow, are stressed as they are in some forms of glaucoma, they considerably up-regulated secretion of a protein called myocilin into the aqueous. The function of this protein is unclear; but since some aqueous humor flows to the posterior of the eye, the effects of myocilin will also be felt by the retinal cells. We have a transgenic mouse that secretes large amounts of myocilin into aqueous humor. In these mice, there is a deposition of myocilin on membranes of certain cells suggesting myocilin might have some signaling functions. This signaling function could explain why stresses that increase intraocular pressures can increase the likelihood for glaucoma, cause the myocilin to be secreted at very high levels by the trabecular meshwork. Myocilin may be important in treating glaucoma. This experiment will determine if myocilin is altering gene expression in the retina. The results should show variations in expression levels and will give us some indication of the pathways that are important to preserve retinal ganglion cells after a diagnosis of glaucoma. Our hypothesis is that myocilin is acting like a signaling protein in the eye. It acts not only in the anterior segment but also in retina as a result of the flow of some aqueous to the back of the eye. This signaling function is protective to certain ocular cells. This function of myocilin may influence cells in the retina and may counter the apoptotic signals in the retinal ganglion cells that occur during glaucoma. Retinas from transgenic mice and from mice of the same strain that do not have the transgene will be dissected. The mice will be three weeks of age. Because of the small size of the retina, samples will be pooled to obtain the RNA necessary to run the microarray. Three control and three transgenic samples will be run and compared with each other. We have data indicating that myocilin is at high levels in the aqueous humor of the transgenic animals.

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

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