Abnormal cell sorting underlies the unique X-linked inheritance of PCDH19 epilepsy

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dc.contributor.authorPederick, D.
dc.contributor.authorRichards, K.
dc.contributor.authorPiltz, S.
dc.contributor.authorKumar, R.
dc.contributor.authorMincheva-Tasheva, S.
dc.contributor.authorMandelstam, S.
dc.contributor.authorDale, R.
dc.contributor.authorScheffer, I.
dc.contributor.authorGecz, J.
dc.contributor.authorPetrou, S.
dc.contributor.authorHughes, J.
dc.contributor.authorThomas, P.
dc.date.issued2018
dc.description.abstractX-linked diseases typically exhibit more severe phenotypes in males than females. In contrast, protocadherin 19 (PCDH19) mutations cause epilepsy in heterozygous females but spare hemizygous males. The cellular mechanism responsible for this unique pattern of X-linked inheritance is unknown. We show that PCDH19 contributes to adhesion specificity in a combinatorial manner such that mosaic expression of Pcdh19 in heterozygous female mice leads to striking sorting between cells expressing wild-type (WT) PCDH19 and null PCDH19 in the developing cortex, correlating with altered network activity. Complete deletion of PCDH19 in heterozygous mice abolishes abnormal cell sorting and restores normal network activity. Furthermore, we identify variable cortical malformations in PCDH19 epilepsy patients. Our results highlight the role of PCDH19 in determining cell adhesion affinities during cortical development and the way segregation of WT and null PCDH19 cells is associated with the unique X-linked inheritance of PCDH19 epilepsy.
dc.description.statementofresponsibilityDaniel T. Pederick, Kay L. Richards, Sandra G. Piltz, Raman Kumar, Stefka Mincheva-Tasheva, Simone A. Mandelstam, Russell C. Dale, Ingrid E. Scheffer, Jozef Gecz, Steven Petrou, James N. Hughes and Paul Q. Thomas
dc.identifier.citationNeuron, 2018; 97(1):59-e5
dc.identifier.doi10.1016/j.neuron.2017.12.005
dc.identifier.issn0896-6273
dc.identifier.issn1097-4199
dc.identifier.orcidKumar, R. [0000-0001-7976-8386]
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]
dc.identifier.urihttp://hdl.handle.net/2440/111071
dc.language.isoen
dc.publisherCELL PRESS
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/400121
dc.rights© 2017 Elsevier Inc.
dc.source.urihttps://doi.org/10.1016/j.neuron.2017.12.005
dc.subjectPCDH19-GCE; cell sorting
dc.titleAbnormal cell sorting underlies the unique X-linked inheritance of PCDH19 epilepsy
dc.typeJournal article
pubs.publication-statusPublished

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