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.

Developmental expression of Neuregulin‐3 in the rat central nervous system

“…NRG3 has been associated with an increased risk for SZ, and multiple behavioral and cognitive abnormalities (Avramopoulos, ). Genetic studies have reported a consistent relationship between single nucleotide polymorphisms (SNPs) located within the first intron of Nrg3 and the SZ endophenotype of delusional behavior (Morar et al, ).…”

“…Neuregulin-3 (Nrg3) is a member of the neuregulin (Nrg1-4) family of growth factors, which play important roles in the developing and mature nervous system (Birchmeier & Bennett, 2016;Grieco, Holmes, & Xu, 2018;Mei & Nave, 2014;Mei & Xiong, 2008). Nrg3 is of particular interest as it has emerged as a candidate risk gene for several neuropsychiatric disorders including bipolar disorder and schizophrenia (SZ) (Avramopoulos, 2018; P. L. Chen et al, 2009;Hayes et al, 2016;Loos et al, 2014;Paterson et al, 2017). Recent studies have also indicated that Nrg3 plays important roles in cortical development (Bartolini et al, 2017) and glutamatergic neurotransmission (Wang et al, 2018).…”

“…NRG3 has been associated with an increased risk for SZ, and multiple behavioral and cognitive abnormalities (Avramopoulos, 2018).…”

In Vitro and In Vivo Models for the Investigation of Potential Drugs Against Schizophrenia

“…Olaya et al [133] generated transgenic mice with forebrain-driven Nrg1 III overexpression (Nrg1 III tg) and stated that these mice exhibited several SZ-relevant behaviors including social and cognitive deficits as well as impaired sensorimotor gating. Finally, there are also reports about the role of neuregulin-3 in SZ [134] which may also be a base of animal genetic models.…”

Genomic landscape of the signals of positive natural selection in populations of Northern Eurasia: A view from Northern Russia

“…The NRG3 and PTPRM genes have been listed as potential targets of natural selection [15,40]. Neuregulin 3 is a key component of the NRG3-ERBB4 pathway, which is involved in the development of several tissues, with strongest effects on the differentiation of the neural system [41]. NRG3 has been implicated as a susceptibility gene for schizophrenia and schizoaffective disorders [41].…”