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Global signaling effects of a schizophrenia-associated missense mutation in neuregulin 1: an exploratory study using whole genome and novel kinome approaches

  • Translational Neurosciences - Original Article
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Abstract

Aberrant neuregulin 1-ErbB4 signaling has been implicated in schizophrenia. We previously identified a novel schizophrenia-associated missense mutation (valine to leucine) in the NRG1 transmembrane domain. This variant inhibits formation of the NRG1 intracellular domain (ICD) and causes decreases in dendrite formation. To assess the global effects of this mutation, we used lymphoblastoid cell lines from unaffected heterozygous carriers (Val/Leu) and non-carriers (Val/Val). Transcriptome data showed 367 genes differentially expressed between the two groups (Val/Val N = 6, Val/Leu N = 5, T test, FDR (1 %), α = 0.05, −log10 p value >1.5). Ingenuity pathway (IPA) analyses showed inflammation and NRG1 signaling as the top pathways altered. Within NRG1 signaling, protein kinase C (PKC)–eta (PRKCH) and non-receptor tyrosine kinase (SRC) were down-regulated in heterozygous carriers. Novel kinome profiling (serine/threonine) was performed after stimulating cells (V/V N = 6, V/L N = 6) with ErbB4, to induce release of the NRG1 ICD, and revealed significant effects of treatment on the phosphorylation of 35 peptides. IPA showed neurite outgrowth (six peptides) as the top annotated function. Phosphorylation of these peptides was significantly decreased in ErbB4-treated Val/Val but not in Val/Leu cells. These results show that perturbing NRG1 ICD formation has major effects on cell signaling, including inflammatory and neurite formation pathways, and may contribute significantly to schizophrenia pathophysiology.

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Acknowledgments

This work was supported in part by K01MH077777 and NARSAD: Brain and Behavior Research Foundation grants awarded to CWB; UT system grant: translational science training across disciplines awarded to KKM. The authors thank Dr. Teresa Johnson-Pais, Dr. Carolina Livi, Yasmin Ench and Mandy Rolando (Genomics core- University of Texas Health Science Center at San Antonio, UTHSCSA) and Dr. Christopher Willey and Dr. Joshua Anderson (Kinome core-University of Alabama, Birmingham) for their services. We thank the families from the CVCR; this research would not be possible without them. The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX, 78229, USA

    Ketan K. Marballi & Robin J. Leach

  2. Department of Psychiatry, Neuroscience Program, South Texas Research Facility, 8403 Floyd Curl Dr., San Antonio, TX, 78229, USA

    Ketan K. Marballi

  3. Department of Psychiatry, School of Medicine, University of Alabama at Birmingham, 1719 6th Avenue South, CIRC 576A, Birmingham, AL, 35294, USA

    Robert E. McCullumsmith & Stefani Yates

  4. Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, 4800 Alberta Ave, El Paso, TX, 79905, USA

    Michael A. Escamilla

  5. School of Biology, University of Costa Rica, San Jose, 2060, Costa Rica

    Henriette Raventos

  6. Department of Psychiatry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX, 78229, USA

    Consuelo Walss-Bass

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  1. Ketan K. Marballi
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Correspondence to Consuelo Walss-Bass.

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Additional file Table S1 – Peptides differentially phosphorylated in Val/Val and Val/Leu cell lines.

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Marballi, K.K., McCullumsmith, R.E., Yates, S. et al. Global signaling effects of a schizophrenia-associated missense mutation in neuregulin 1: an exploratory study using whole genome and novel kinome approaches. J Neural Transm 121, 479–490 (2014). https://doi.org/10.1007/s00702-013-1142-6

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