In vivo and in vitro genetic evidence of involvement of neuregulin 1 in immune system dysregulation

Ketan Marballi, Marlon P. Quinones, Fabio Jimenez, Michael A. Escamilla, Henriette Raventós, Maria Clara Soto-Bernardini, Seema S. Ahuja, Consuelo Walss-Bass

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


Neuregulin 1 (NRG1) has been implicated in several disorders including breast cancer, multiple sclerosis, and schizophrenia. Also, recent evidence suggests that NRG1 may play a role in regulation of inflammation and immune system response. We therefore hypothesized that a schizophrenia-associated missense mutation (valine to leucine) we identified within the transmembrane region of NRG1 would also be linked to immune dysregulation. We used plasma samples from families carrying the mutation to measure levels of antibodies to 41 autoimmune markers and six cytokines (IL-1b, IL-6, IL-10, IL-8, IL-12p70, and TNF-α) and used these levels as quantitative traits to evaluate association with the NRG1 mutation, using FBAT. Next, we used Epstein-Barr virus-transformed B cells from heterozygous mutation carriers and wild-type individuals to evaluate protein and mRNA cytokine expression in vitro using quantitative PCR and ELISA assays. In vivo, increased levels of 25 autoimmune markers as well as elevated levels of cytokines were significantly associated with the NRG1 mutation. In vitro, we observed a significant increase in protein secretion levels of IL-6, TNF-α, and IL-8 in mutation carriers compared with controls. At the mRNA level, we observed a significant increase in IL-6 expression, while IL-4 levels appeared to be down-regulated in heterozygous individuals compared with wild-type controls. This is the first report of association of a NRG1 mutation with immune dysregulation. This study could contribute towards understanding the role of NRG1 in the pathogenesis of schizophrenia and other disorders in which inflammation plays an important role.

Original languageEnglish (US)
Pages (from-to)1133-1141
Number of pages9
JournalJournal of Molecular Medicine
Issue number11
StatePublished - Nov 2010


  • Autoantibodies
  • Cytokines
  • Immune system
  • Inflammation
  • Lymphoblastoid cell lines
  • Neuregulin-1

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)


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