Aberrant gene expression yet undiminished retinal ganglion cell genesis in iPSC-derived models of optic nerve hypoplasia.

Autor:	Aparicio JG; The Vision Center and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA., Hopp H; The Vision Center and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA., Harutyunyan N; The Vision Center and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA., Stewart C; The Vision Center and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA., Cobrinik D; The Vision Center and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.; Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.; USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA., Borchert M; The Vision Center and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.; USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Jazyk:	angličtina
Zdroj:	Ophthalmic genetics [Ophthalmic Genet] 2024 Feb; Vol. 45 (1), pp. 1-15. Date of Electronic Publication: 2024 Jan 26.
DOI:	10.1080/13816810.2023.2253902
Abstrakt:	Background: Optic nerve hypoplasia (ONH), the leading congenital cause of permanent blindness, is characterized by a retinal ganglion cell (RGC) deficit at birth. Multifactorial developmental events are hypothesized to underlie ONH and its frequently associated neurologic and endocrine abnormalities; however, environmental influences are unclear and genetic underpinnings are unexplored. This work investigates the genetic contribution to ONH RGC production and gene expression using patient induced pluripotent stem cell (iPSC)-derived retinal organoids (ROs). Materials and Methods: iPSCs produced from ONH patients and controls were differentiated to ROs. RGC genesis was assessed using immunofluorescence and flow cytometry. Flow-sorted BRN3+ cells were collected for RNA extraction for RNA-Sequencing. Differential gene expression was assessed using DESeq2 and edgeR. PANTHER was employed to identify statistically over-represented ontologies among the differentially expressed genes (DEGs). DEGs of high interest to ONH were distinguished by assessing function, mutational constraint, and prior identification in ONH, autism and neurodevelopmental disorder (NDD) studies. Results: RGC genesis and survival were similar in ONH and control ROs. Differential expression of 70 genes was identified in both DESeq2 and edgeR analyses, representing a ~ 4-fold higher percentage of DEGs than in randomized study participants. DEGs showed trends towards over-representation of validated NDD genes and ONH exome variant genes. Among the DEGs, RAPGEF4 and DMD had the greatest number of disease-relevant features. Conclusions: ONH genetic background was not associated with impaired RGC genesis but was associated with DEGs exhibiting disease contribution potential. This constitutes some of the first evidence of a genetic contribution to ONH.
Databáze:	MEDLINE
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