DISC1
View/Edit Human | View/Edit Mouse |
Disrupted in schizophrenia 1 is a
Discovery
In 1970, researchers from the University of Edinburgh performing cytogenetic research on a group of juvenile offenders in Scotland found an abnormal translocation in chromosome 1 of one of the boys, who also displayed characteristics of an affective psychological disorder.[8] After this initial observation, the boy's family was studied and it was found that 34 out of 77 family members displayed the same translocation. According to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (or DSM-IV) criteria, sixteen of the 34 individuals identified as having the genetic mutation were diagnosed with psychiatric problems. In contrast, five of the 43 unaffected family members were identified to have psychological indispositions. The psychiatric illnesses observed in the family ranged from schizophrenia and major depression to bipolar disorder and adolescent conduct disorder (which the original research subject had).[9] After studying this large Scottish family for four generations, in 2000, this gene was given the name "DISC1". The name was derived from the basis of the molecular nature of the mutation: the translocation directly disrupts the gene.[5]
Importance of genetic studies
The implication of genetics in psychiatric illnesses is not unique to schizophrenia, though the heritability of schizophrenia has been calculated as high as 80%.[10] The continued research of the family following the discovery of the translocation yielded statistical analysis of the probability of observing the simultaneous occurrence, or co-inheritance, of psychological conditions and the translocation. This concept was measured quantitatively using the LOD, or logarithm of the odds value.[11] The higher the LOD value, the stronger the correlation between the presence of the translocation and given disease(s) is thought to be. The LOD for the chromosome 1 translocation and identification of schizophrenia alone in the Scottish family was found to be 3.6.[11] The LOD value of the translocation and a broader number of diagnoses (including schizophrenia, schizoaffective disorder, bipolar affective disorder, and recurrent major depression) was found to be 7.1.[11]
Besides large familial-based studies in which the pedigrees of various family members are examined, twin studies have also been a source of support for researchers in the investigation of DISC1.[10] In a meta-analysis of twin studies, twelve out of fourteen were found to support the fact that from a genetic perspective, schizophrenia is a complex trait that depends on both genetic and environmental factors.[10] Such findings have encouraged researchers to continue with both macro-analysis of the disorders affecting individuals with the mutation, as well as explore the micro-level.
Gene location and transcription
The DISC1 gene is situated at
Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[14]
DISC1 homologues have been identified in all major vertebrate families including the
Protein structure and subcellular distribution
The protein encoded by this gene is predicted to contain a
The protein locates to the
Function
Many studies have provided insight into the normal function of the DISC1 protein, though much remains to be clearly defined. DISC1 is functionally involved in several processes that regulate
DISC1 functions through a rich protein-protein interaction network, named the "DISC1 interactome" by researchers.[18] Among its known interaction partners are 14-3-3ε, LIS1 and the PDE4B enzyme.[19] DISC1 may play an important role in neuroplasticity via interactions with molecules of the cytoskeleton and centrosome, such as NUDEL and LIS1. The protein also enables the activity of dynein, a microtubule protein. Controlling transport of microtubules is involved in neuronal migration, neurite outgrowth, and axon formation.[20]
DISC1 is highly expressed during critical periods of brain development, particularly in the embryonic ventricular and subventricular zones of the cortex, where neural progenitor cells are found. This localization suggests that DISC1 is an important regulator of embryonic and adult neurogenesis, and may regulate proliferation and/or differentiation. Levels of the protein in cycling neural progenitor cells affects whether they differentiate into neurons or remain as progenitors.[18] Expression profile is highest in the hippocampus during development and remains highly expressed in the adult dentate gyrus and olfactory bulb, regions where adult neurogenesis is present.[20] DISC1 has also been shown to regulate tempo of neuronal integration into the brain and guidance of positioning of new neurons.[20]
Due to localization of the protein found at the synapse, DISC1 is also likely to play a key role in postsynaptic density, however this novel role is not yet fully understood.[18]
Protein interactions
The DISC1 protein has no known enzymatic activity; rather it exerts its effect on multiple proteins through
DISC1
DISC1 has been shown to self-associate, to form
ATF4/ATF5
ATF4 and ATF5 are members of the leucine zipper activating transcription factor / CREB family. They are known to bind to and regulate the function of GABAB receptors in synapses and are involved in signal transduction from the cell membrane to the nucleus. Both proteins interact with DISC1 and GABAB receptors via their second C-terminal leucine zipper domain, therefore DISC1 is able to regulate GABAB receptor function through its interaction with ATF4/ATF5.[21][24]
FEZ1
DISC1 participates in neurite outgrowth through its interaction with the fasciculation and elongation protein ζ-1 (FEZ1). FEZ1 is a mammalian homolog of the C. elegans UNC-76 protein involved in axonal outgrowth and fasciculation. The C-terminal region of FEZ1 (aa 247–392) is required for interaction with DISC1. A DISC1 region (aa 446–633), containing two stretches with coiled-coil-forming potential is critical for its interaction with FEZ1.[25] DISC1-FEZ1 interaction is enhanced during neuro-differentiation, and expression of the FEZ1-binding domain of DISC1 has a dominant negative effect on neurite outgrowth, which implies co-operation of DISC1 and FEZ1 in this process.[21]
Kalirin-7
The DISC1 protein plays a role in the process of regulating spine form and function through its interactions with
MAP1A
DISC1 shows strong interaction with the microtubule-associated protein
NDEL1/NUDEL
DISC1 is localized to the centrosome, the primary microtubule organizing center of the cell, via interaction with nuclear distribution gene homologue-like 1 (NDEL1, also called NUDEL), where it is part of a protein complex involved in cytoskeletal processes of neuronal migration, including nucleokinesis and neurite outgrowth. NUDEL is also known to play a role in axon regeneration and has an additional DISC1-modulated function as a cysteine endopeptidase. Localization of NUDEL to axons is dependent on expression of DISC1.[21] NUDEL binds to a 100 amino acid domain of DISC1 (aa 598–697) containing a coiled coil domain and a leucine zipper. The amino acid domain of NUDEL that binds DISC1 is the carboxyl terminal 100 amino acids of the protein (aa 241–345), which contains a cytoplasmic dynein binding site.[24]
PCM1/Pericentriolar material
The protein Pericentriolar Material 1 (PCM1) which is associated with cilia development in the CNS interacts directly with the Disrupted-In-Schizophrenia 1 (DISC1) and calmodulin 1 (CALM1) proteins. Kamiya et al. have shown that PCM1, DISC1 and BBS4 can all disrupt neuronal organisation in the mouse when their expression is down-regulated.[26] Markers at the pericentriolar material 1 gene (PCM1) have shown genetic association with schizophrenia in several schizophrenia case control studies.[27][28] Resequencing of the genomic DNA from research volunteers who had inherited haplotypes associated with schizophrenia showed a threonine an isoleucine mis-sense mutation in exon 24 which may change the structure and function of PCM1 (rs370429).[29] This mutation was found only as a heterozygote in ninety eight research subjects with schizophrenia and controls out of a total sample of 2,246 case and control research subjects. Amongst the ninety eight carriers of rs370429 sixty seven were affected with schizophrenia. The same alleles and haplotypes were associated with schizophrenia in both London and Aberdeen samples. Another potential aetiological base pair change in PCM1 was rs445422 which altered a splice site signal. A further mutation, rs208747, was shown by electrophoretic mobility shift assays to create or destroy a promoter transcription factor site. Five further non-synonymous changes in exons were also found. Given the number and identity of the haplotypes associated with schizophrenia further aetiological base pair changes must exist within and around the PCM1 gene.[29] The findings in relation to PCM1 support the role of DISC1 also being a susceptibility locus for schizophrenia.
Other interactions include:
Clinical implications
Aberrations of DISC1 are considered a generalized risk factor in major psychiatric diseases and have also been implicated in memory deficits and abnormal patterns of brain activity.[17][30] DISC1 translocation increases the risk of developing schizophrenia, bipolar disorder, or major depression by about 50-fold in comparison to the general population.[18] Efforts to model DISC1 disease biology in transgenic mice, Drosophila, and zebrafish have provided psychiatric disease implications related to DISC1 mutations.[18] However, no specific variant is consistently associated with development of mental disorders, indicating allelic heterogeneity in psychiatric disease. The impact of variants in the DISC1 gene on expression and protein function is not yet clearly defined and associated variants are not necessarily causative.[31]
Schizophrenia
Schizophrenia affects 1% of the general population and is highly heritable, providing an indication of a genetic basis.[20] DISC1 has been associated with neurological abnormalities such as delusions, deficits in long term and working memory, diminution of gray matter volume in hippocampal and prefrontal regions.[20] These abnormalities are also seen as symptoms of schizophrenia. As DISC1 function is involved in neurogenesis and neuroplasticity, vulnerability to schizophrenia may involve dysfunction in the hippocampus, a brain region in which adult neurogenesis occurs.[20] Mice expressing the dominant-negative form of DISC1 have been shown to be increasingly susceptible to impaired reality testing, a hallmark of psychosis.[32]
Autism and Asperger's syndrome
In 2008, a
Transgenic model organism strains generated with mutated or absent DISC1 suggest that the gene may contribute to at least some autistic abnormalities.[30] Mice with lowered levels of DISC1 expression exhibit abnormal response to electrical stimulation, a decrease of dopamine synthesis, and an inability to filter unnecessary sensory information. Studies of expression of mutant DISC1 prenatally and postnatally have demonstrated varying effects, indicating the possibility that early postnatal expression of mutant DISC1 causes features of autism. Many more studies are necessary to confirm these suggestions.[30]
Bipolar disorder
Linkage studies in extended families multiply affected with bipolar disorder also provide evidence for DISC1 as a genetic factor in the etiology of bipolar disorder.[33] In 1998, a follow-up study was conducted of the large Scottish family in which DISC1 was first discovered. Additional family members with the original translocation who developed major psychotic illness, including bipolar disorder, were identified.[33]
Research directions
As DISC1 investigation continues to be an emerging area of study, many unanswered questions regarding the biological function of the protein and its implications in psychiatric disorders remain. In depth understanding of DISC1 as a genetic risk factor for psychiatric disorders provides a possible target for developing new drug therapies and preventative measures.[33] The pathways regulated by DISC1 interaction may provide possible avenues for therapeutic opportunities to reverse related deficits.[18] Definitive genetic architecture, risk distribution, and their correlation with prognosis is crucial to determining response to new drug treatments.[31]
In addition to DISC1, the antisense partner has been identified as DISC2, a noncoding RNA gene that may be involved in regulating the gene locus. However, structure and function of DISC2 remain unknown and may provide insight into how DISC1 is regulated.[31]
Rare mutations in DISC1 other than the original translocation have been discovered and require further investigation.[18] Furthermore, posttranslational processing and its effect on isoform expression, which also contributes to protein function and may be involved in some forms of disease, remains to be studied.[18][31] The ability to predict the impact of different types of mutations on protein function and resulting psychiatric phenotype is crucial for the development of targeted treatments.[31]
Family studies continue to provide an important approach towards deepening understanding of the biological nature of the gene and its clinical implications. While the original Scottish family in which DISC1 was discovered is still being considered, other familial populations in different countries have also become the focus of research in the past decade. In 2005, an American family was found to also possess a frameshift mutation in the DISC1 gene, which again co-segregated with schizophrenia and schizoaffective disorder.[34] Characterized by a deletion of four base-pairs, the mutation was found in two siblings, one with schizophrenia and the other with schizoaffective disorder. Similar studies have also been done with Taiwanese and Finnish families.[34]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000162946 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000043051 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 10814723.
- PMID 26974950.
- S2CID 199518630.
- PMID 11443544.
- S2CID 30908484.
- ^ PMID 14662550.
- ^ S2CID 36081296.
- PMID 19805229.
- ^ S2CID 24153531.
- ^ "Entrez Gene: DISC1 disrupted in schizophrenia 1".
- ^ PMID 12573262.
- PMID 21852244.
- ^ ISBN 978-0-521-51733-1.[page needed]
- ^ PMID 19828788.
- PMID 19300510.
- ^ PMID 19519407.
- ^ PMID 21195721.
- PMID 18400883.
- PMID 19583211.
- ^ PMID 12812986.
- PMID 12874605.
- PMID 18762586.
- S2CID 25843064.
- PMID 16894060.
- ^ PMID 19048012.
- ^ a b c d e Chi KR (1 March 2010). "Clinical, animal studies probe DISC1's role in autism". Spectrum.
- ^ PMID 17912248.
- PMID 31150554.
- ^ PMID 11450173.
- ^ PMID 15940305.
Further reading
- Blackwood DH, Muir WJ (2004). "Clinical phenotypes associated with DISC1, a candidate gene for schizophrenia". Neurotoxicity Research. 6 (1): 35–41. S2CID 24180414.
- Porteous DJ, Thomson P, Brandon NJ, Millar JK (Jul 2006). "The genetics and biology of DISC1--an emerging role in psychosis and cognition". Biological Psychiatry. 60 (2): 123–31. S2CID 36920488.
- Lipska BK, Mitkus SN, Mathew SV, Fatula R, Hyde TM, Weinberger DR, et al. (2006). "Functional genomics in postmortem human brain: abnormalities in a DISC1 molecular pathway in schizophrenia". Dialogues in Clinical Neuroscience. 8 (3): 353–7. PMID 17117617.
- Seki N, Ohira M, Nagase T, Ishikawa K, Miyajima N, Nakajima D, et al. (Oct 1997). "Characterization of cDNA clones in size-fractionated cDNA libraries from human brain". DNA Research. 4 (5): 345–9. PMID 9455484.
- Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, et al. (May 2000). "Disruption of two novel genes by a translocation co-segregating with schizophrenia". Human Molecular Genetics. 9 (9): 1415–23. PMID 10814723.
- Ekelund J, Hovatta I, Parker A, Paunio T, Varilo T, Martin R, et al. (Jul 2001). "Chromosome 1 loci in Finnish schizophrenia families". Human Molecular Genetics. 10 (15): 1611–7. PMID 11468279.
- Hennah W, Varilo T, Kestilä M, Paunio T, Arajärvi R, Haukka J, et al. (Dec 2003). "Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects". Human Molecular Genetics. 12 (23): 3151–9. PMID 14532331.
- Millar JK, Christie S, Porteous DJ (Nov 2003). "Yeast two-hybrid screens implicate DISC1 in brain development and function". Biochemical and Biophysical Research Communications. 311 (4): 1019–25. PMID 14623284.
- Brandon NJ, Handford EJ, Schurov I, Rain JC, Pelling M, Duran-Jimeniz B, et al. (Jan 2004). "Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders". Molecular and Cellular Neurosciences. 25 (1): 42–55. S2CID 21261573.
- Miyoshi K, Asanuma M, Miyazaki I, Diaz-Corrales FJ, Katayama T, Tohyama M, et al. (May 2004). "DISC1 localizes to the centrosome by binding to kendrin". Biochemical and Biophysical Research Communications. 317 (4): 1195–9. PMID 15094396.