ReviewNeuregulin 1 and Schizophrenia: Genetics, Gene Expression, and Neurobiology
Section snippets
The NRG1 Gene and Its Isoforms
The human NRG1 gene is located at chromosome 8p13. It spans approximately 1.4 megabases, has more than 20 exons and several large introns (Figure 1), and gives rise to at least 15 isoforms. All isoforms contain a core EGF domain, EGFc, encoded by exon E130, but other elements of the protein are variable. (In the absence of an agreed or definitive exon numbering system for NRG1, exons are labeled as described by Steinthorsdottir et al [2004], with the number denoting their length in nucleotides;
The 8p Locus
Chromosome 8p, especially a 30cM region around 8p21.1-22, has been implicated as a locus harboring one or more schizophrenia genes by several linkage studies (Blouin et al 1998, Brzustowicz et al 1999, Gurling et al 2001, Kendler et al 1996, Levinson et al 1996, Liu et al 2005, Pulver et al 1995, Stefansson et al 2002). As with all other putative schizophrenia loci, there have also been equivocal and negative findings (DeLisi et al 2000, Kaufmann et al 1998, Kunugi et al 1996, Shaw et al 1998,
Neuregulin 1 Expression and Function in Schizophrenia
As noted earlier, an alteration in NRG1 expression, and thence NRG1 function, is the putative molecular mechanism mediating the influence of NRG1 upon schizophrenia risk. Recent data provide initial experimental support for, and refinement of, this possibility (Table 4).
Hashimoto et al (2004) studied types I–III NRG1 transcripts in the dorsolateral prefrontal cortex and found increased type I NRG1 mRNA in schizophrenia. The elevation was present relative to the other NRG1 isoforms and to three
Summary
There is now substantial but not incontrovertible evidence that genetic variation in NRG1 is associated with schizophrenia (Table 3). Proving this beyond all reasonable doubt will be intrinsically difficult, for two main reasons—which apply not only to NRG1 but to other putative susceptibility genes for psychiatric disorders (Colhoun et al 2003, Harrison and Weinberger 2005, Paige et al 2003). The first reason relates to the genetic architecture. Schizophrenia is a complex genetic disorder with
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