X-linked intellectual disability gene CASK regulates postnatal brain growth in a non-cell autonomous manner

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dc.contributor.authorSrivastava, Sarikaen
dc.contributor.authorMcMillan, Ryan P.en
dc.contributor.authorWillis, Jefferyen
dc.contributor.authorClark, Helen R.en
dc.contributor.authorChavan, Vrushalien
dc.contributor.authorLiang, Chenen
dc.contributor.authorZhang, Haiyanen
dc.contributor.authorHulver, Matthew W.en
dc.contributor.authorMukherjee, Konarken
dc.date.accessioned2019-06-03T21:03:09Zen
dc.date.available2019-06-03T21:03:09Zen
dc.date.issued2016-03-31en
dc.description.abstractThe phenotypic spectrum among girls with heterozygous mutations in the X-linked intellectual disability (XLID) gene CASK (calcium/calmodulin-dependent serine protein kinase) includes postnatal microcephaly, ponto-cerebellar hypoplasia, seizures, optic nerve hypoplasia, growth retardation and hypotonia. Although CASK knockout mice were previously reported to exhibit perinatal lethality and a 3-fold increased apoptotic rate in the brain, CASK deletion was not found to affect neuronal physiology and their electrical properties. The pathogenesis of CASK associated disorders and the potential function of CASK therefore remains unknown. Here, using Cre-LoxP mediated gene excision experiments; we demonstrate that deleting CASK specifically from mouse cerebellar neurons does not alter the cerebellar architecture or function. We demonstrate that the neuron-specific deletion of CASK in mice does not cause perinatal lethality but induces severe recurrent epileptic seizures and growth retardation before the onset of adulthood. Furthermore, we demonstrate that although neuron-specific haploinsufficiency of CASK is inconsequential, the CASK mutation associated human phenotypes are replicated with high fidelity in CASK heterozygous knockout female mice (CASK(+/-)). These data suggest that CASK-related phenotypes are not purely neuronal in origin. Surprisingly, the observed microcephaly in CASK(+/-) animals is not associated with a specific loss of CASK null brain cells indicating that CASK regulates postnatal brain growth in a non-cell autonomous manner. Using biochemical assay, we also demonstrate that CASK can interact with metabolic proteins. CASK knockdown in human cell lines cause reduced cellular respiration and CASK(+/-) mice display abnormalities in muscle and brain oxidative metabolism, suggesting a novel function of CASK in metabolism. Our data implies that some phenotypic components of CASK heterozygous deletion mutation associated disorders represent systemic manifestation of metabolic stress and therefore amenable to therapeutic intervention.en
dc.description.sponsorshipNIH award 1R01EY024712-01A1en
dc.format.extent18 pagesen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1186/s40478-016-0295-6en
dc.identifier.issue30en
dc.identifier.urihttp://hdl.handle.net/10919/89725en
dc.identifier.volume4en
dc.language.isoenen
dc.publisherBMCen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectCASKen
dc.subjectMAGUKen
dc.subjectCerebellar hypoplasiaen
dc.subjectNon-cell autonomousen
dc.subjectX-linked intellectual disabilityen
dc.subjectMetabolismen
dc.titleX-linked intellectual disability gene CASK regulates postnatal brain growth in a non-cell autonomous manneren
dc.title.serialActa Neuropathologica Communicationsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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Destination Area: Adaptive Brain and Behavior (ABB)