the disrupted in schizophrenia 1 ( disc1 ) gene is a 414.3 kb gene located on chromosomal region 1q42.2 , and consists of 13 exons .
disc1 was originally identified as a candidate gene for schizophrenia in a large scottish family , in which a balanced translocation involving chromosomes 1 and 11 was strongly linked to schizophrenia , schizoaffective disorder , bipolar affective disorder , and recurrent , major depression . in this family
, carriers of the translocation were found to have reduced p300 amplitude , which is observed in some patients with schizophrenia .
subsequent association studies identified numerous polymorphisms in the disc1 gene associated with schizophrenia and affective disorders , although different , polymorphisms / haplotypes in various regions of the gene were implicated in these studies . 
  in the adult mouse brain ,
disc1 is expressed widely , including in the olfactory bulb , cortex , hippocampus , hypothalamus , cerebellum , and brain stem . during development ,
disc1 protein is detected at all stages , from embryonic day 10 ( elo ) to 6 months old , with two significant peaks of protein expression of one of the disc1 isoforms at e13.5 and postnatal day 35 .
interestingly , these time points correspond to periods of active neurogenesis and puberty in the mouse .
these results suggest , that disc1 may play a critical role in brain development , lending support to the neurodevelopmental hypothesis of schizophrenia . 

disc1 encodes an 854-amino acid ( aa ) protein , which shows no homology to other known proteins and little homology between species .
this amino - acid sequence predicts that the protein disc1 may act as a scaffolding protein with multiple binding motifs , facilitating formation of protein complexes .
the n -terminus ( aa 1 - 347 ) contains nuclear localization signals , whereas the c - terminus ( aa 348 - 854 ) appears to be important , for microtubule and centrosomal targeting,17 - 19 although no centrosomal localization has been detected so far for the native protein .
although the precise function of disc1 in the brain is unknown , a number of disc1 -interacting partners have been identified , including fasciculation and elongation protein zeta-1 ( fez1 ) , nuclear distribution element - like ( nudel ) , and lissencephaly 1 ( lis1 ) , which are known to play a role in neuronal development and functioning .
altered interactions between disc1 and its binding partners are currently being investigated in order to understand more accurately the biology of disc1 as a schizophrenia susceptibility gene .
in an effort to understand the cellular function of disc1 , yeast - two hybrid studies have been used to identify molecular interactors of disc1 .
it , was found that , disc1 has numerous binding partners , including nudel , fez1 , activating transcription factor ( att ' ) 4/5 , and microtubule - associated protein 1 a ( mapi a ) .
nudel is a component of a pathway involved in cytoplasmic dynein movement , and is involved in neurofilament assembly , neuronal migration , and development of neurite morphology .
overexpression of truncated disc1 protein inhibits neurite outgrowth in pci 2 cells , suggesting that the disc1-nudel complex may be involved in neuronal outgrowth .
the hypothetical peptide product , resulting from the scottish translocation removes the interaction domain for nudel .
recently , it has been shown that nudel oligopeptidase activity is under tight , regulation through binding to disc1 , since a mutation very close to the disc1-binding site of nudel abolishes this activity .
interestingly , nudel cleaves a number of neuropeptides in vitro , some of which have previously been implicated in the pathophysiology of schizophrenia , including neurotensin ( nt ) .
nt receptor agonists may be potential antipsychotics ; thus , inhibition of nudel could lead to increase in local concentration of nt , which may have an antipsychotic effect .
altered subcellular distribution of disc1 has been reported in patients with psychosis and alcohol / substance abuse , with increased ratios of nuclear to cytoplasmic disc1 protein levels in patients .
cell culture studies in cortical neurons have found evidence that disc1 may colocalize with mitochondrial markers , and that its subcellular targeting is independent of the nudel - binding site .
hayashi et al have also demonstrated that disc1 and nudel bind in a neurodevelopmentally regulated manner and form a trimolecular complex with another protein , lis1 .
lis1 is involved in neuronal migration and corticogenesis . although the function of this complex is currently unknown , it .
another interacting partner of disc1 is fez1 , which is a mammalian homologue of the caenorhabditis elegans unc-76 protein , involved in axonal outgrowth and fasciculation .
miyoshi et al demonstrated that disc1 participates in neurite extension through its c - terminal interaction with fez1 .
the chromosomal location for fez1 was previously implicated in a schizophrenia linkage analysis , although results from different , populations vary in significance .
a modest association between schizophrenia and fez1 polymorphisms has been detected in a subset of japanese patients . 

in our laboratory , we have tested the hypothesis that , altered expression of disc1 , and/or its molecular partners nudel , fez1 , and lis1 may underlie its pathogenic role in schizophrenia and explain its genetic association .
we examined the expression of disc1 and these selected binding partners in postmortem human brain .
we found no difference in the expression of disc1 mrna in schizophrenia , and no association with previously identified risk snps ( all f values < 1.5 , all p values > 0.2 ) .
disc1 immunoreactivity was significantly , albeit modestly ( by approximately 20% ) , increased in the hippocampus of patients with schizophrenia : f(1,73)=3.6 , p=0.05 .
however , the expression of nudel , fez1 , and lis1 mrna was each significantly reduced in schizophrenic tissue in both the dorsolateral prefrontal cortex and hippocampus and the expression of each gene showed association with a high risk disc1 polymorphism ( all p values < 0.05 ) .
these data implicate genetically linked abnormalities in the disc1 molecular pathway in the pathophysiology of schizophrenia . given its role in brain development and plasticity via .
its interaction with a. number of different proteins , disc1 remains a. candidate gene for schizophrenia , and an understanding of its exact mechanistic role in neuronal pathways may shed more light on the disease .
schizophrenia is a devastating neuropsychiatrie disorder , the genetics of which has been under extensive investigation for several decades . despite being an exceedingly complex disease in terms of both etiology and pathogenesis , recent research is finally shedding light on schizophrenia susceptibility genes .
prominent , among them are the genes comt , dtnbp1 , grm3 , disc1 , nrg1 , akt1 , gad1 , rgs4 , and drd2 .
disc1 and its binding partners fez1 , nudel , and lis1 are involved in cytoplasmic dynein movement , neurofilament assembly , neuronal migration , and neurite morphology , and may play a role in the neurodevelopmental deficits observed in schizophrenia . although the precise neurobiological cause of schizophrenia continues to be unknown , the abundance of evidence regarding susceptibility genes for schizophrenia can not be dismissed .
identification of the molecular and cellular mechanisms that link susceptibility genes to the neurobiological functioning of the brain continues to be a major focus of research . as evidence for
may be determined that these genes operate in a convergent molecular pathway affecting neural development and synaptic plasticity .
the disruption of multiple genes within this pathway may lead to the development of schizophrenia .
 the disrupted in schizophrenia 1 ( disc1 ) gene has been identified as a schizophrenia susceptibility gene based on linkage and single nucleotide polymorphism ( snp ) association studies and clinical data , suggesting that risk snps impact on hippocampal structure and function . 
 we hypothesized that altered expression of disc1 andlor its molecular partners ( nuclear distribution element - like [ nudel ] , fasciculation and elongation protein zeta-1 [ fez1 ] , and lissencephaly 1 [ l1s1 ] ) may underlie its pathogenic role in schizophrenia and explain its genetic association . 
 we examined the expression of disc1 and its binding partners in the hippocampus and dorsolateral prefrontal cortex of postmortem human brains of schizophrenic patients and controls . 
 we found no difference in the expression of disc1 mrna in schizophrenia , and no association with previously identified risk snps , however , the expression of nudel , fez1 , and lis1 vas significantly reduced in tissue from schizophrenic subjects , and the expression of each showed association with high - risk disc1 polymorphisms . 
 these data suggest involvement of genetically linked abnormalities in the disc1 molecular pathway in the pathophysiology of schizophrenia . 
D1SC1 gene
DISC1 molecular pathway
Abnormalities in a 
Conclusions