Journal article

Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy

Daniel 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, Paul Q Thomas

NEURON | CELL PRESS | Published : 2018

Abstract

X-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 ..

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Grants

Awarded by NHMRC grant


Funding Acknowledgements

We thank Dr. L. Luo (Stanford University) and members of the Thomas lab for discussion and comments. We thank the patients and their families for participating in our research. D.T.P. was supported by an Australian Government Research Training Scholarship. This work was supported by an NHMRC grant (400121) and the PCDH19 Alliance. The supplemental materials contain additional data.