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Updated 3 January 2007
Printable version

Live Discussion: The DISC1 Pathway in Major Mental Illness: Clinical, Genetic and Biological Evidence—Current Status and Future Prospects

David Porteous

Ishizuka et al. 2006

Porteous et al. 2006

The past year has seen a flurry of activity—on both the experimental and speculative fronts—surrounding disrupted-in-schizophrenia 1 (DISC1). To help make some sense of the recent studies and reviews, David Porteous of the University of Edinburgh helped us convene a virtual “roundtable” on the topic on January 23, 2007. If you missed the discussion, we invite you to read the background text below, not to mention the suggested articles (at left), comments left before the chat, and especially, the chat transcript.

Any comments you contribute to this discussion will appear in our What's New section and in our newsletter (See also the SRF news stories mentioned in the text below, as well as an SRF meeting report on DISC1 presentations at the Neuroscience 2006 meeting).

Special Update: Following the posting of the transcript, we asked Akira Sawa of Johns Hopkins University, who was unable to join us for the live chat, to serve as a discussant. He obliged by reviewing some of the interesting discussion, as well as mentioning questions that were not brought up. Please read his review.

Our thanks to Biological Psychiatry and Elsevier for granting open access to these two papers:

Ishizuka K, Paek M, Kamiya A, Sawa A. A review of Disrupted-In-Schizophrenia-1 (DISC1): neurodevelopment, cognition, and mental conditions. Biol Psychiatry. 2006 Jun 15;59(12):1189-97. Abstract

View comments by:
Judith GaultPosted 23 January 2007

Porteous DJ, Thomson P, Brandon NJ, Millar JK. The genetics and biology of DISC1--an emerging role in psychosis and cognition. Biol Psychiatry. 2006 Jul 15;60(2):123-31. Abstract

View Transcript of Live Discussion — Posted 25 February 2007

View Comments By:
Akira Sawa — Posted 16 January 2007
Mikhail Pletnikov — Posted 19 January 2007
Nick Brandon — Posted 19 January 2007
Christopher Ross — Posted 20 January 2007
Chris Carter — Posted 20 January 2007
David J. Porteous — Posted 23 January 2007
Katherine E. Burdick — Posted 23 January 2007
John Roder — Posted 23 January 2007
Akira Sawa — Posted 16 March 2007

Background Text
By David Porteous

The purpose of this forum is to discuss recent clinical, genetic, and biochemical evidence linking DISC1 and DISC1 interactors to susceptibility to major mental illness (see recent reviews by Ishikura et al. (2006), Biological Psychiatry, 59, 1189-1197; Porteous et al. (2006); and Porteous and Millar (2006)).

DISC1 was discovered as a novel gene at the breakpoint on chromosome 1q42 in a single Scottish family in which a balanced translocation between chromosomes 1 and 11 co-segregates with major mental illness, diagnosed as schizophrenia, bipolar disorder, or recurrent major depression. Recently, a number of independent genetic studies in various populations have implicated the DISC1 locus by linkage or association for schizophrenia, schizoaffective disorder, bipolar disorder, and major depression. Other studies of clinical and normal variation in measures of cognition and brain structure and function have also implicated a role for DISC1.

In parallel, our knowledge and understanding of DISC1 has increased (see SRF related news story). DISC1 is widely expressed, but developmentally regulated, with high levels of brain expression during prenatal neurogenesis and in the adult hippocampus. Downregulation of Disc1 expression by RNAi in the mouse neonate has been reported to result in abnormal neuronal migration and arborization. The 129 strain of mouse has a mutant form of Disc1, and this is associated with a deficit in working memory (see SRF related news story).

There is now a large body of direct evidence to show that DISC1 acts as a “hub” or scaffold protein, interacting with multiple protein partners, several of which are already known to play important roles in neurodevelopment, neurotransmission and signaling, the cytoskeleton, and centrosomal function.

The purpose of this forum is to review the current data, identify gaps or ambiguities in the current evidence, consider some unanswered questions of immediate relevance to the field, and discuss how these might best be addressed by prospective studies.

Some provisional questions:

1. What are the nature and effects of DISC1 mutations?
2. How is DISC1 expression regulated?
3. What are the consequences of aberrant DISC1 expression at the cellular and developmental level?
4. How, when, and where is DISC1 expression altered in the brains of subjects with mental illness?
5. What is the role of DISC1 in determining brain development?
6. What is the mechanism for DISC1 regulating cognitive processes, learning, and memory?
7. Can mouse models of the DISC1 pathway provide developmental and mechanistic insights not possible in patient studies? 8. Does DISC1 identify a target pathway for rational drug development in the treatment of psychosis and mood disorder?

Comments on Online Discussion
Comment by:  Akira Sawa, SRF Advisor
Submitted 16 January 2007 Posted 16 January 2007

I have been impressed by the recent paper in Molecular...  Read more

View all comments by Akira Sawa

Comment by:  Mikhail Pletnikov
Submitted 19 January 2007 Posted 19 January 2007

I sometimes cannot help thinking that without DISC1 we...  Read more

View all comments by Mikhail Pletnikov

Comment by:  Nick Brandon (Disclosure)
Submitted 19 January 2007 Posted 19 January 2007

It's an exciting time for research around DISC1. There is...  Read more

View all comments by Nick Brandon

Comment by:  Christopher Ross
Submitted 20 January 2007 Posted 20 January 2007

DISC1’s increasingly extensive interactome and rich cell...  Read more

View all comments by Christopher Ross

Comment by:  Chris Carter
Submitted 20 January 2007 Posted 20 January 2007

DISC1 as a Hub Gene

Camargo and colleagues, in...  Read more

View all comments by Chris Carter

Comment by:  David J. Porteous, SRF Advisor
Submitted 23 January 2007 Posted 23 January 2007

Several of you have posted interesting comments which I...  Read more

View all comments by David J. Porteous

Comment by:  Katherine E. Burdick
Submitted 23 January 2007 Posted 23 January 2007

There has been a growing interest in the DISC1 gene, as...  Read more

View all comments by Katherine E. Burdick

Comment by:  John Roder
Submitted 23 January 2007 Posted 23 January 2007

Being newcomers to the field, we reviewed it a few years...  Read more

View all comments by John Roder

Comment by:  Akira Sawa, SRF Advisor
Submitted 16 March 2007 Posted 16 March 2007

On behalf of all the investigators who believe DISC1 is a...  Read more

View all comments by Akira Sawa
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