Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ERα)

Duyen H. Pham, Chuan C. Tan, Claire C. Homan, Kristy L. Kolc, Mark A. Corbett, Dale McAninch, Archa H. Fox, Paul Q. Thomas, Raman Kumar, Jozef Gecz

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22 Citations (Scopus)


De novo and inherited mutations of X-chromosome cell adhesionmolecule protocadherin 19 (PCDH19) cause frequent, highly variable epilepsy, autism, cognitive decline and behavioural problems syndrome. Intriguingly, hemizygous nullmales are not affected while heterozygous females are, contradicting established X-chromosome inheritance. The disease mechanism is not known. Cellular mosaicism is the likely driver. We have identified p54nrb/NONO, amultifunctional nuclear paraspeckle protein with known roles in nuclear hormone receptor gene regulation, as a PCDH19 protein interacting partner. Using breast cancer cells we show that PCDH19-NONO complex is a positive co-regulator of ERa-mediated gene expression. Expression of mutant PCDH19 affects at least a subset of known ERα-regulated genes. These data are consistent with our findings that genes regulated by nuclear hormone receptors and those involved in themetabolism of neurosteroids in particular are dysregulated in PCDH19-epilepsy girls and affected mosaicmales. Overall we define and characterize a novelmechanism of gene regulation driven by PCDH19, which is mediated by paraspeckle constituent NONO and is ERα-dependent. This PCDH19-NONO-ERa axis is of relevance not only to PCDH19-epilepsy and its comorbidities but likely also to ERα and generally nuclear hormone receptor-associated cancers.

Original languageEnglish
Pages (from-to)2042-2052
Number of pages11
JournalHuman molecular genetics
Issue number11
Publication statusPublished or Issued - 1 Jun 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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