Non-Cell Autonomous Roles for CASK in Optic Nerve Hypoplasia

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dc.contributor.authorKerr, Aliciaen
dc.contributor.authorPatel, Paras A.en
dc.contributor.authorLaConte, Leslie E. W.en
dc.contributor.authorLiang, Chenen
dc.contributor.authorChen, Ching-Kangen
dc.contributor.authorShah, Veeralen
dc.contributor.authorFox, Michael A.en
dc.contributor.authorMukherjee, Konarken
dc.contributor.departmentBiological Sciencesen
dc.contributor.departmentFralin Biomedical Research Instituteen
dc.contributor.departmentVirginia Tech Carilion School of Medicineen
dc.date.accessioned2020-03-24T12:25:27Zen
dc.date.available2020-03-24T12:25:27Zen
dc.date.issued2019en
dc.description.abstractPURPOSE. Heterozygous mutations in the essential X-linked gene CASK associate with optic nerve hypoplasia (ONH) and other retinal disorders in girls. CASKþ/ heterozygous knockout mice with mosaic CASK expression exhibit ONH with a loss of retinal ganglion cells (RGCs) but no changes in retinal morphology. It remains unclear if CASK deficiency selectively affects RGCs or also affects other retinal cells. Furthermore, it is not known if CASK expression in RGCs is critical for optic nerve (ON) development and maintenance. METHODS. The visual behavior of CASKþ/ mice was assessed and electroretinography (ERG) was performed. Using a mouse line with a floxed CASK gene that expresses approximately 40% CASK globally in all cells (hypomorph) under hemizygous and homozygous conditions, we investigated effects of CASK reduction on the retina and ON. CASK then was completely deleted from RGCs to examine its cell-autonomous role. Finally, for the first time to our knowledge, we describe a hemizygous CASK missense mutation in a boy with ONH. RESULTS. CASKþ/ heterozygous mutant mice display reduced visual contrast sensitivity, but ERG is indistinguishable from wildtype. CASK hypomorph mice exhibit ONH, but deletion of CASK from RGCs in this background does not exacerbate the condition. The boy with ONH harbors a missense mutation (p.Pro673Leu) that destabilizes CASK and weakens the crucial CASK–neurexin interaction. CONCLUSIONS. Our results demonstrate that mosaic or global reduction in CASK expression and/or function disproportionately affects RGCs. CASK expression in RGCs does not appear critical for cell survival, indicating a noncell autonomous role for CASK in the development of ON.en
dc.description.sponsorshipSupported by grants from the National Institutes of Health (NIH; Bethesda, MD, USA) Grants EY026930 and EY002520 (C-KC). Work in the Fox and Mukherjee laboratories is supported by the NIH Grants EY024712 (KM), AI124677 (MAF), and EY021222 (MAF).en
dc.identifier.doihttps://doi.org/ 10.1167/iovs.19-27197en
dc.identifier.urihttp://hdl.handle.net/10919/97443en
dc.identifier.volume60en
dc.language.isoen_USen
dc.publisherARVOen
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectoptic nerve hypoplasiaen
dc.subjectCASKen
dc.subjectretinal ganglion cellsen
dc.subjectnon-cell autonomousen
dc.titleNon-Cell Autonomous Roles for CASK in Optic Nerve Hypoplasiaen
dc.title.serialInvestigative Ophthalmology & Visual Scienceen
dc.typeArticle - Refereeden

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