Complete loss of the X-linked gene CASK causes severe cerebellar degeneration

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dc.contributor.authorPatel, Paras A.en
dc.contributor.authorHegert, Juliaen
dc.contributor.authorCristian, Ingriden
dc.contributor.authorKerr, Aliciaen
dc.contributor.authorLaConte, Leslie E. W.en
dc.contributor.authorFox, Michael A.en
dc.contributor.authorSrivastava, Sarikaen
dc.contributor.authorMukherjee, Konarken
dc.date.accessioned2024-02-01T13:44:21Zen
dc.date.available2024-02-01T13:44:21Zen
dc.date.issued2022-02-11en
dc.description.abstractBackground Heterozygous loss of X-linked genes like CASK and MeCP2 (Rett syndrome) causes developmental delay in girls, while in boys, loss of the only allele of these genes leads to epileptic encephalopathy. The mechanism for these disorders remains unknown. CASK-linked cerebellar hypoplasia is presumed to result from defects in Tbr1-reelin-mediated neuronal migration. Method Here we report clinical and histopathological analyses of a deceased 2-month-old boy with a CASK-null mutation. We next generated a mouse line where CASK is completely deleted (hemizygous and homozygous) from postmigratory neurons in the cerebellum. Result The CASK-null human brain was smaller in size but exhibited normal lamination without defective neuronal differentiation, migration or axonal guidance. The hypoplastic cerebellum instead displayed astrogliosis and microgliosis, which are markers for neuronal loss. We therefore hypothesise that CASK loss-induced cerebellar hypoplasia is the result of early neurodegeneration. Data from the murine model confirmed that in CASK loss, a small cerebellum results from postdevelopmental degeneration of cerebellar granule neurons. Furthermore, at least in the cerebellum, functional loss from CASK deletion is secondary to degeneration of granule cells and not due to an acute molecular functional loss of CASK. Intriguingly, female mice with heterozygous deletion of CASK in the cerebellum do not display neurodegeneration. Conclusion We suggest that X-linked neurodevelopmental disorders like CASK mutation and Rett syndrome are pathologically neurodegenerative; random X-chromosome inactivation in heterozygous mutant girls, however, results in 50% of cells expressing the functional gene, resulting in a non-progressive pathology, whereas complete loss of the only allele in boys leads to unconstrained degeneration and encephalopathy.en
dc.description.versionAccepted versionen
dc.format.extentPages 1044-1057en
dc.format.extent14 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1136/jmedgenet-2021-108115en
dc.identifier.eissn1468-6244en
dc.identifier.issn0022-2593en
dc.identifier.issue11en
dc.identifier.orcidSrivastava, Sarika [0000-0001-9634-5510]en
dc.identifier.orcidMukherjee, Konark [0000-0002-6922-9554]en
dc.identifier.orcidFox, Michael [0000-0002-1649-7782]en
dc.identifier.orcidLaConte, Leslie [0000-0003-3747-0973]en
dc.identifier.otherjmedgenet-2021-108115 (PII)en
dc.identifier.pmid35149592en
dc.identifier.urihttps://hdl.handle.net/10919/117772en
dc.identifier.volume59en
dc.language.isoenen
dc.publisherBMJen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/35149592en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectpaediatricsen
dc.subjectpathologyen
dc.subjectnervous system diseasesen
dc.subjectcongenitalen
dc.subjecthereditaryen
dc.subjectneonatal diseases and abnormalitiesen
dc.subjectcentral nervous system diseasesen
dc.subject.meshAnimalsen
dc.subject.meshHumansen
dc.subject.meshMiceen
dc.subject.meshCerebellar Diseasesen
dc.subject.meshNeurodegenerative Diseasesen
dc.subject.meshRett Syndromeen
dc.subject.meshInfanten
dc.subject.meshFemaleen
dc.subject.meshMaleen
dc.subject.meshGenes, X-Linkeden
dc.subject.meshGuanylate Kinasesen
dc.titleComplete loss of the X-linked gene CASK causes severe cerebellar degenerationen
dc.title.serialJournal of Medical Geneticsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2022-01-13en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Scienceen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Science/COS T&R Facultyen
pubs.organisational-group/Virginia Tech/Science/School of Neuroscienceen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicineen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/Internal Medicineen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/VTC School of Medicine - Instr Pgmsen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/Psychiatry and Behavioral Medicineen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/Pediatricsen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/Pediatrics/General Pediatricsen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/Pediatrics/General Pediatrics/Secondary Appointment-Pediatricsen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/Psychiatry and Behavioral Medicine/Secondary Appointment-Psychiatry and Behavioral Medicineen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/Internal Medicine/Secondary Appointment- Internal Medicineen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/Internal Medicine/Internal Med-Subgroupen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Biomedical Research Institute at VTCen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/Pediatrics/Secondary Appointments-Pediatricsen

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