A t(1;11) translocation linked to schizophrenia and affective disorders gives rise to aberrant chimeric DISC1 transcripts that encode structurally altered, deleterious mitochondrial proteins

Abstract

Disrupted-In-Schizophrenia 1 (DISC1) was identified as a risk factor for psychiatric illness through its disruption by a balanced chromosomal translocation, t(1;11)(q42.1;q14.3), that co-segregates with schizophrenia, bipolar disorder and depression. We previously reported that the translocation reduces DISC1 expression, consistent with a haploinsufficiency disease model. Here we report that, in lymphoblastoid cell lines, the translocation additionally results in the production of abnormal transcripts due to the fusion of DISC1 with a disrupted gene on chromosome 11 (DISC1FP1/Boymaw). These chimeric transcripts encode abnormal proteins, designated CP1, CP60 and CP69, consisting of DISC1 amino acids 1–597 plus 1, 60 or 69 amino acids, respectively. The novel 69 amino acids in CP69 induce increased α-helical content and formation of large stable protein assemblies. The same is predicted for CP60. Both CP60 and CP69 exhibit profoundly altered functional properties within cell lines and neurons. Both are predominantly targeted to mitochondria, where they induce clustering and loss of membrane potential, indicative of severe mitochondrial dysfunction. There is currently no access to neural material from translocation carriers to confirm these findings, but there is no reason to suppose that these chimeric transcripts will not also be expressed in the brain. There is thus potential for the production of abnormal chimeric proteins in the brains of translocation carriers, although at substantially lower levels than for native DISC1. The mechanism by which inheritance of the translocation increases risk of psychiatric illness may therefore involve both DISC1 haploinsufficiency and mitochondrial deficiency due to the effects of abnormal chimeric protein expression.GenBank accession numbers: DISC1FP1 (EU302123), Boymaw (GU134617), der 11 chimeric transcript DISC1FP1 exon 2 to DISC1 exon 9 (JQ650115), der 1 chimeric transcript DISC1 exon 4 to DISC1FP1 exon 4 (JQ650116), der 1 chimeric transcript DISC1 exon 6 to DISC1FP1 exon 3a (JQ650117).

Disrupted in schizophrenia 1 (DISC1) is a constituent of the mammalian mitochondrial contact site and cristae organizing system (MICOS) complex, and is essential for oxidative phosphorylation

“…Although hDISC1 is enriched in the mitochondria (5), the relationship of its mitochondrial function with the pathogenesis of the disease is still under debate. Overexpression of truncated hDISC1 isoforms induced abnormal mitochondrial morphologies, indicating changes in mitochondrial dynamics such as fission and fusion (4,6,9). Our hDISC1 depleted cells exhibited an overload of fragmented mitochondria, indicative of excess of fission or loss of fusion.…”

“…Growing evidences suggest that part of the pathological components of the disease can be attributable to mitochondrial function abnormalities, supported by recent findings suggesting mitochondrial roles to Disrupted in Schizophrenia-1 (DISC1). DISC1 was identified in a balanced reciprocal chromosomal translocation t(1;11) (q42;q14) that results in DISC1 truncated forms, such as the D597-854, co-segregating with schizophrenia and other major affective disorders in a large Scottish family (1)(2)(3)(4). DISC1 is a multi-compartmentalized protein found in the cytoplasm, centrosome, nuclei and mostly enriched in mitochondria (5).…”

“…It has been observed that modulation of DISC1 protein levels induces morphological abnormalities (6), causes deficiencies in important mitochondrial enzyme activities like NADH and L-Monoamine Oxidase (MAO)-A (7), and impairs mitochondrial trafficking throughout the axons (8,9). Moreover, overexpression of the resultant truncated proteins of the translocation identified in the Scottish family translates in aggregation of abnormal proteins in the mitochondria that induces clusterization and loss of mitochondrial membrane potential (mDW) (4). DISC1 acts as scaffold binding a number of other proteins.…”

DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders

“…The Scottish t (1;11) family is exceptional because of its size, longitudinal clinical follow-up and detailed molecular genetic study. The foundational finding is of a t(1;11) translocation that disrupts three genes: DISC1, DISC2 and DISC1FP, alters DISC1 expression and results in production of abnormal fusion transcripts [39,40]. Direct disruption of DISC1 impacts on neurodevelopment, glutamate-signalling, cognitive ability and liability to psychiatric disorder [41][42][43][44][45][46][47][48][49][50].…”

Analysis of Shared Haplotypes amongst Palauans Maps Loci for Psychotic Disorders to 4q28 and 5q23-q31

“…More relevant to this study, some variants have been implicated due to their segregation with affection status in extended pedigrees. A classic example is a balanced chromosomal translocation, t(1;11)(q42.1;q14.3), disrupting DISC1 , which generates a fusion product of DISC1 and Boymaw [14,15]. This rare variant shows significant co-segregation with schizophrenia, bipolar disorder and depression in a large family [16].…”