The paper by Yu et al. places another tick next to the NPAS3 candidate gene. Since the discovery of its disruption by a chromosomal translocation in a mother and daughter—both diagnosed with schizophrenia—it has cropped up several times in case-control association and mutation screens. This transcription factor has also accrued a catalogue of functional characteristics that align it well with potential schizophrenia pathologies. These include behavioral, neurodevelopmental, metabolic, and hippocampal neurogenesis deficits detected in a mouse knockout model, and a cellular pathology that includes mitochondrial fragility (Pickard et al., 2006; Sha et al., 2012; Pieper et al., 2010).
This latest chapter in the NPAS3 story details how the authors carried out resequencing in families densely affected with schizophrenia diagnoses. They identified a missense mutation (rs146677388) that changed the valine residue normally at this site into isoleucine in one such family. Although not large enough to generate a significant LOD score, the mutation obeys co-segregation with the diagnosis of schizophrenia in the family. However, it should be noted that all non-carriers in the family were diagnosed with lesser psychiatric conditions. In follow-on studies, the authors demonstrated that the variant is indeed rare, but not entirely exclusive to the family or a diagnosis of schizophrenia.
The NPAS3 gene is both very highly conserved at the protein level (down to fish) while also containing intronic regions that show strong evidence for rapid evolution in humans (Pollard et al., 2006). The identified V->I change is actually located within a span of four residues that show a breakdown in conservation in fish and amphibians. Therefore, as ever, the problem becomes one of trying to demonstrate that a rare variant has a pathological effect. The first steps on that path are taken in the paper when the authors demonstrate an in-vitro inhibitory effect of the mutation on neurite outgrowth in comparison to the wild-type NPAS3.
What next? More mutations and positive associations would certainly add supporting evidence, but the real struggle will be to unify the disparate nature of the phenotypes linked with NPAS3 dysfunction at the level of a specific pathology—one that must involve altered regulation of this transcription factor’s target genes.
Pickard BS, Pieper AA, Porteous DJ, Blackwood DH, Muir WJ. The NPAS3 gene--emerging evidence for a role in psychiatric illness. Ann Med . 2006 ; 38(6):439-48. Abstract
Sha L, Macintyre L, Machell JA, Kelly MP, Porteous DJ, Brandon NJ, Muir WJ, Blackwood DH, Watson DG, Clapcote SJ, Pickard BS. Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3. Mol Psychiatry . 2012 Mar ; 17(3):267-79. Abstract
Pieper AA, Xie S, Capota E, Estill SJ, Zhong J, Long JM, Becker GL, Huntington P, Goldman SE, Shen CH, Capota M, Britt JK, Kotti T, Ure K, Brat DJ, Williams NS, MacMillan KS, Naidoo J, Melito L, Hsieh J, De Brabander J, Ready JM, McKnight SL. Discovery of a proneurogenic, neuroprotective chemical. Cell . 2010 Jul 9 ; 142(1):39-51.
Pollard KS, Salama SR, Lambert N, Lambot MA, Coppens S, Pedersen JS, Katzman S, King B, Onodera C, Siepel A, Kern AD, Dehay C, Igel H, Ares M, Vanderhaeghen P, Haussler D. An RNA gene expressed during cortical development evolved rapidly in humans. Nature . 2006 Sep 14 ; 443(7108):167-72. Abstract
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