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

Daniel T. Pederick, Kay L. Richards, Sandra G. Piltz, Simone A. Mandelstam, Russell C. Dale, Ingrid E. Scheffer, Jozef Gecz, Steve Petrou, James N. Hughes, Paul Q. Thomas

Research output: Contribution to journalArticlepeer-review

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 highly specific combinatorial adhesion codes such that mosaic expression of Pcdh19 in heterozygous female mice leads to striking sorting between WT PCDH19- and null PCDH19-expressing cells 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 specific adhesion codes during cortical development and how disruption of these codes is associated with the unique X-linked inheritance of PCDH19 epilepsy.

Original languageEnglish
JournalUnknown Journal
DOIs
Publication statusPublished - 20 Aug 2017

Keywords

  • Adhesion molecules
  • cell sorting
  • cell-cell adhesion code
  • cortical development
  • epilepsy
  • PCDH19-GCE
  • Protocadherin 19
  • Protocadherins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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