Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia

Abstract

Two overlapping and antiparallel genes on chromosome 1, Disrupted In Schizophrenia 1 and 2 (DISC1 and DISC2), are disrupted by a (1;11)(q42.1;q14.3) translocation which segregates with schizophrenia through at least four generations of a large Scottish family. Consequently, these genes are worthy of further investigation as candidate genes potentially involved in the aetiology of major psychiatric illness. We have constructed a contiguous clone map of PACs and cosmids extending across at least 400 kb of the chromosome 1 translocation breakpoint region and this has provided the basis for examination of the genomic structure of DISC1. The gene consists of thirteen exons, estimated to extend across at least 300 kb of DNA. The antisense gene DISC2 overlaps with exon 9. Exon 11 contains an alternative splice site that removes 66 nucleotides from the open reading frame. The final intron of DISC1 belongs to the rare AT-AC class of introns. We have also mapped marker DIS251 in close proximity to DISC1, localising the gene within a critical region identified by several independent studies. Information regarding the structure of the DISC1 gene will facilitate assessment of its involvement in the aetiology of major mental illness in psychotic individuals unrelated to carriers of the translocation. Molecular Psychiatry (2001) 6, 173-178.

Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia

“…The translocation disrupts a gene termed disrupted-in-schizophrenia 1 (DISC1) on chromosome 1. 5,7,9 Linkage and association at the DISC1 locus have been demonstrated for psychiatric illness in several populations, [10][11][12][13][14][15][16][17] suggesting wider relevance of DISC1.…”

“…5,6 An alternative approach is to study families in which schizophrenia and allied psychiatric disorders segregate with cytogenetic abnormalities. 7 In these families, a single major genetic defect could confer susceptibility to psychiatric illnesses. One large Scottish pedigree was identified, 8 in which a balanced (1:11) (q42.1; q14.3) translocation co-segregates with major psychiatric disorders (LOD scores = 4-7).…”

Does disrupted-in-schizophrenia (DISC1) generate fusion transcripts?

“…4,5 The function of the DISC2 was presumed to be involved in the regulation of DISC1 expression. 4,5 Nevertheless, no gene was found to be disrupted at the break point in chromosome 11q14.3.…”

A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder

“…On the opposite strand, the translocation falls in the middle of DISC2, an apparently untranslated gene that has no known function. 5,8 Other genetic studies have indicated that factors at the DISC1 locus may contribute to the risk of psychiatric disorders. Linkage 9,10 and association 11 of schizophrenia to 1q42 has been reported in Finnish populations, and linkage was also detected in a Taiwanese population.…”

“…Further, as a translocation, it is difficult to exclude the possibility of effects at the other locus of translocation (11q14.3), although genes have not been identified at this location. 5,8 It also remains possible that the translocation could influence other genes in the vicinity of DISC1 27 or that disruption of DISC2 could be of etiologic significance. Given these uncertainties, identification of additional DISC1 mutations that segregate with schizophrenia would substantially strengthen the case that DISC1 is an important factor in at least some cases of schizophrenia.…”