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Neuron. 2018 Jan 3;97(1):59-66.e5. doi: 10.1016/j.neuron.2017.12.005.

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

Author information

1
School of Biological Sciences and Robinson Research Institute, The University of Adelaide, Adelaide, SA 5005, Australia.
2
Florey Institute of Neuroscience and Mental Health and Department of Medicine Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC 3010, Australia.
3
School of Medicine and Robinson Research Institute, The University of Adelaide, Adelaide, SA 5005, Australia.
4
Department of Paediatrics, The University of Melbourne, Melbourne, VIC 3010, Australia; Department of Radiology, The University of Melbourne, Melbourne, VIC 3010, Australia; Department of Medical Imaging, Royal Children's Hospital, Florey Neurosciences Institute, Parkville, VIC 3052, Australia.
5
Institute for Neuroscience and Muscle Research, University of Sydney, Sydney, NSW 2006, Australia.
6
Florey Institute of Neuroscience and Mental Health and Department of Medicine Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC 3010, Australia; The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, VIC 3084, Australia.
7
School of Biological Sciences and Robinson Research Institute, The University of Adelaide, Adelaide, SA 5005, Australia; School of Medicine and Robinson Research Institute, The University of Adelaide, Adelaide, SA 5005, Australia; South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia.
8
School of Biological Sciences and Robinson Research Institute, The University of Adelaide, Adelaide, SA 5005, Australia; School of Medicine and Robinson Research Institute, The University of Adelaide, Adelaide, SA 5005, Australia; South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia. Electronic address: paul.thomas@adelaide.edu.au.

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 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.

KEYWORDS:

PCDH19-GCE; adhesion molecules; cell sorting; cell-cell adhesion code; cortical development; epilepsy; protocadherin 19; protocadherins

PMID:
29301106
DOI:
10.1016/j.neuron.2017.12.005
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