DISC Pathway Genetics and Biology

Background

We are studying a large multi-generational Scottish family in which a balanced translocation (1;11)(q42;q14) co-segregates with schizophrenia, bipolar disorder and recurrent major depression, with a maximum LOD score of 7.1, equating to odds of ~10million-to-one against this pattern of inheritance occurring by chance. Individuals carrying the translocation are therefore at high risk of developing major psychiatric illness. Our study is based upon the hypothesis that the translocation has altered expression of a gene (or genes) leading to elevated risk of developing major psychiatric illness.

This translocation directly disrupts two overlapping genes named Disrupted In SChizophrenia 1 and 2 (DISC1 and DISC2). DISC1 encodes a large protein lacking any significant homology to other proteins, while DISC2 is apparently a large non-coding RNA gene, and may belong to the class of non-coding antisense RNA genes thought to regulate expression of the sense gene.

Since both DISC1 and DISC2 are directly disrupted by the translocation, it is extremely likely that one or both of these genes are a major cause of the psychiatric illness suffered by affected translocation carriers. There is also strong independent genetic evidence supporting the involvement of this locus in conferring susceptibility to psychiatric illness in several populations world-wide, including that of Scotland. Moreover, many studies have demonstrated links between DISC1 genotype and cognitive functions, including normal cognitive aging, in both affected and unaffected individuals. Study of DISC1 and DISC2 therefore provides an important opportunity to understand critical molecular mechanisms involved in brain function and dysfunction, and how their dysregulation contributes to the symptoms of major psychiatric disorders.

DISC1 and haploinsufficiency

The location of the breakpoint within DISC1 predicts two main hypothetical disease mechanisms: The translocation may lead to either production of a truncated DISC1 protein, and a possible dominant-negative effect, or to abolition of expression from the disrupted allele. Using lymphoblastoid cell lines derived from translocation carriers and family members with a normal karyotype, we have demonstrated that levels of DISC1 transcripts are reduced in translocation carriers. This correlates with reduced expression of all known DISC1 protein isoforms in translocation carriers and absence of any detectable abnormal truncated DISC1 protein. Thus DISC1 haploinsufficiency is the most likely mechanism by which inheritance of the translocation confers susceptibility to major psychiatric illness.

DISC1 and cAMP signalling

We recently demonstrated that phosphodiesterase 4B (PDE4B) binds directly to DISC1. PDE4B is a member of the family of type 4 phosphodiesterases that regulate cAMP signalling by hydrolysing cAMP. PDE4s are orthologous to Drosophila Dunce, a protein required for learning and memory processes, and are directly inhibited by the antidepressant rolipram. Moreover, PDE4B was identified as a genetic risk factor for schizophrenia (by Ben Pickard in this laboratory) because it is directly disrupted by a balanced chromosomal translocation in a patient with schizophrenia and a cousin with psychosis. This interaction between two independently identified genetic risk factors suggests that we have identified a molecular pathway of direct clinical relevance.

PDE4s have a modular structure consisting (in long isoforms) of a unique N-terminus thought to be involved in subcellular targeting, two upstream regulatory domains (UCR1 & UCR2) and a catalytic domain. Catalytic activity is regulated by PKA phosphorylation of UCR1 and ERK phosphorylation of the catalytic domain. The head domain of DISC1 binds directly to the regulatory UCR2 domain of PDE4B. This binding critically depends upon cellular cAMP levels, with PDE4B dissociating in an active state when cyclic AMP levels are elevated. Thus, DISC1 may sequester PDE4B in an inactive form until it is required by the cell to switch off cAMP signalling, at which time PDE4B is activated and released. DISC1 may therefore have an essential role in regulating cAMP signalling.

We are continuing to investigate the roles of DISC1 & DISC2 in brain function with the aim of determining what goes wrong in the brains of psychiatric patients.

Selected References

Brandon et al (2004) Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Molecular & Cellular Neuroscience 25: 42-55
Callicott et al (2005) Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. PNAS 102: 8627-8632
Camargo et al (2006) Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Molecular Psychiatry Epub
Hennah et al (2003) Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Human Molecular Genetics 12: 3151-3159
Kamiya et al (2005) A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nature Cell Biology 7: 1167-1178
Koike et al (2006) Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. PNAS 103: 3693-3697
Myoshi et al (2003) Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. Molecular Psychiatry 8: 685-694
Ogawa et al (2006) A functional link between Disrupted-In-Schizophrenia 1 and the eukaryotic translation initiation factor 3. BBRC 338: 771-776
Schurov et al (2004) Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment. Molecular Psychiatry 9: 1100-1110

	Introduction Bioinformatics Funding Publications Contact	DISC Pathway Genetics and Biology Background We are studying a large multi-generational Scottish family in which a balanced translocation (1;11)(q42;q14) co-segregates with schizophrenia, bipolar disorder and recurrent major depression, with a maximum LOD score of 7.1, equating to odds of ~10million-to-one against this pattern of inheritance occurring by chance. Individuals carrying the translocation are therefore at high risk of developing major psychiatric illness. Our study is based upon the hypothesis that the translocation has altered expression of a gene (or genes) leading to elevated risk of developing major psychiatric illness. This translocation directly disrupts two overlapping genes named Disrupted In SChizophrenia 1 and 2 (DISC1 and DISC2). DISC1 encodes a large protein lacking any significant homology to other proteins, while DISC2 is apparently a large non-coding RNA gene, and may belong to the class of non-coding antisense RNA genes thought to regulate expression of the sense gene. Since both DISC1 and DISC2 are directly disrupted by the translocation, it is extremely likely that one or both of these genes are a major cause of the psychiatric illness suffered by affected translocation carriers. There is also strong independent genetic evidence supporting the involvement of this locus in conferring susceptibility to psychiatric illness in several populations world-wide, including that of Scotland. Moreover, many studies have demonstrated links between DISC1 genotype and cognitive functions, including normal cognitive aging, in both affected and unaffected individuals. Study of DISC1 and DISC2 therefore provides an important opportunity to understand critical molecular mechanisms involved in brain function and dysfunction, and how their dysregulation contributes to the symptoms of major psychiatric disorders. DISC1 and haploinsufficiency The location of the breakpoint within DISC1 predicts two main hypothetical disease mechanisms: The translocation may lead to either production of a truncated DISC1 protein, and a possible dominant-negative effect, or to abolition of expression from the disrupted allele. Using lymphoblastoid cell lines derived from translocation carriers and family members with a normal karyotype, we have demonstrated that levels of DISC1 transcripts are reduced in translocation carriers. This correlates with reduced expression of all known DISC1 protein isoforms in translocation carriers and absence of any detectable abnormal truncated DISC1 protein. Thus DISC1 haploinsufficiency is the most likely mechanism by which inheritance of the translocation confers susceptibility to major psychiatric illness. DISC1 and cAMP signalling We recently demonstrated that phosphodiesterase 4B (PDE4B) binds directly to DISC1. PDE4B is a member of the family of type 4 phosphodiesterases that regulate cAMP signalling by hydrolysing cAMP. PDE4s are orthologous to Drosophila Dunce, a protein required for learning and memory processes, and are directly inhibited by the antidepressant rolipram. Moreover, PDE4B was identified as a genetic risk factor for schizophrenia (by Ben Pickard in this laboratory) because it is directly disrupted by a balanced chromosomal translocation in a patient with schizophrenia and a cousin with psychosis. This interaction between two independently identified genetic risk factors suggests that we have identified a molecular pathway of direct clinical relevance. PDE4s have a modular structure consisting (in long isoforms) of a unique N-terminus thought to be involved in subcellular targeting, two upstream regulatory domains (UCR1 & UCR2) and a catalytic domain. Catalytic activity is regulated by PKA phosphorylation of UCR1 and ERK phosphorylation of the catalytic domain. The head domain of DISC1 binds directly to the regulatory UCR2 domain of PDE4B. This binding critically depends upon cellular cAMP levels, with PDE4B dissociating in an active state when cyclic AMP levels are elevated. Thus, DISC1 may sequester PDE4B in an inactive form until it is required by the cell to switch off cAMP signalling, at which time PDE4B is activated and released. DISC1 may therefore have an essential role in regulating cAMP signalling. We are continuing to investigate the roles of DISC1 & DISC2 in brain function with the aim of determining what goes wrong in the brains of psychiatric patients. Selected References Brandon et al (2004) Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Molecular & Cellular Neuroscience 25: 42-55 Callicott et al (2005) Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. PNAS 102: 8627-8632 Camargo et al (2006) Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Molecular Psychiatry Epub Hennah et al (2003) Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Human Molecular Genetics 12: 3151-3159 Kamiya et al (2005) A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nature Cell Biology 7: 1167-1178 Koike et al (2006) Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. PNAS 103: 3693-3697 Myoshi et al (2003) Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. Molecular Psychiatry 8: 685-694 Ogawa et al (2006) A functional link between Disrupted-In-Schizophrenia 1 and the eukaryotic translation initiation factor 3. BBRC 338: 771-776 Schurov et al (2004) Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment. Molecular Psychiatry 9: 1100-1110
	Updated: Wed, 22nd September, 2010