Neuregulin 3 and its roles in schizophrenia risk and presentation

Abstract

Neuregulins, a four-member family of epidermal growth factor-like signaling molecules, have been studied for over two decades. They were first implicated in schizophrenia in 2002 with the detection of linkage and association at the NRG1 locus followed after a few years by NRG3. However, the associations with disease have not been very consistently observed. In contrast, association of NGR3 variants with disease presentation, specifically the presence of delusions, has been more consistent. This appears to be mediated by quantitative changes in the alternative splicing of the gene, which has also been consistently observed. Additional diseases and phenotypes, psychiatric or not, have also been connected with NRG3. These results demonstrate two important aspects of behavioral genetics research. The first is that if we only consider simple risk and fail to examine the details of each patient's individual phenotype, we will miss important insights on the disease biology. This is an important aspect of the goals of precision medicine. The second is that the functional consequences of variants are often more complex than simple alterations in levels of transcription of a particular gene, including, among others, regulation of alternative splicing. To accurately model and understand the biological consequences of phenotype-associated genetic variants, we need to study the biological consequences of each specific variant. Simply studying the consequences of a null allele of the orthologous gene in a model system, runs the risk of missing the many nuances of hypomorphic and/or gain of function variants in the genome of interest.

Keywords: NRG3; delusions; gene expression; neuregulin; psychosis; schizophrenia.

Figure 1

The NRG3 gene as it appears on the UCSC genome browser (build hg38). Six alternative transcripts with their ENSEMBLE IDs and an antisense transcript are shown in the GENCODE v.24 track. SNPs discussed in this review are shown: schizophrenia associations in red, delusion factor associations in blue and others in green.

Figure 2

Data from GTEx on the expression of NRG3 across tissues

Figure 3

Domains of NRG3 as described by Zhang et. Amino acid positions are shown above. H/Ph: N-terminal hydrophobic segment, S/T rich: serine/threonine-rich domain, TM: predicted transmembrane domain.

Figure 4

Downstream processing after binding of NRG3 to ERBB4 receptors. After binding ERBB4 is activated by autophosphorylation and phosphorylates other targets resulting in activation of ADAM17 which sheds its extracellular domain and Gamma-secretase which releases its intracellular domain. The latter translocates to the nucleus where it participates in transcriptional regulation.

Figure 5

Linkage Disequilibrium between NRG3 SNPs mentioned in this review and shown in Figure 1. R-squared is above the diagonal and D-prime below, and higher values are highlighted red and green respectively. Dashes indicate no data due to SNP distances >500 Kb