Schizophrenia Research Forum - A Catalyst for Creative Thinking

Of Mice and Men: Human Chromosome 17 Sequence Published

25 April 2006. Chromosome 17, which started evolutionary life as half of a mouse chromosome, makes its debut in the April 20 issue of Nature, sequenced by a multi-institutional team led by Michael Zody and Chad Nussbaum of the Broad Institute of Harvard University and Massachusetts Institute of Technology, in Cambridge. The stretch of 17p11 to q25 has been implicated in linkage scans for schizophrenia, and several specific genes have become suspects in schizophrenia and/or mood disorders, including the gene for 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP, see SRF related news story) and for the serotonin transporter (5-HTT or SERT).

Also in residence is LIS1, mutations of which cause the developmental disorder lissencephaly. In this case, there is suspicion by association—the Lis1 protein (see SRF related news story) has been reported to form complexes with disrupted in schizophrenia 1 (DISC1). Also on chromosome 17, there are genes associated with other diseases that can feature psychosis, including genes for huntingtin-associated protein and tau. Tau is one of the two proteins that accumulate in Alzheimer disease, and mutations in tau also cause frontotemporal dementia, a hereditary disorder that in the early stages often mimics schizophrenia, before the symptoms change to look more like a classic dementia.

Some Fun Facts about chromosome 17 from the paper: "Chromosome 17 is unusual among the human chromosomes in many respects. It is the largest human autosome with orthology to only a single mouse chromosome, mapping entirely to the distal half of mouse chromosome 11. Chromosome 17 is rich in protein-coding genes, having the second-highest gene density in the genome. It is also enriched in segmental duplications, ranking third in density among the autosomes."—Hakon Heimer.

Reference:
Zody MC, Garber M, Adams DJ, Sharpe T, Harrow J, Lupski JR, Nicholson C, Searle SM, Wilming L, Young SK, Abouelleil A, Allen NR, Bi W, Bloom T, Borowsky ML, Bugalter BE, Butler J, Chang JL, Chen CK, Cook A, Corum B, Cuomo CA, de Jong PJ, Decaprio D, Dewar K, Fitzgerald M, Gilbert J, Gibson R, Gnerre S, Goldstein S, Grafham DV, Grocock R, Hafez N, Hagopian DS, Hart E, Norman CH, Humphray S, Jaffe DB, Jones M, Kamal M, Khodiyar VK, Labutti K, Laird G, Lehoczky J, Liu X, Lokyitsang T, Loveland J, Lui A, Macdonald P, Major JE, Matthews L, Mauceli E, McCarroll SA, Mihalev AH, Mudge J, Nguyen C, Nicol R, O'leary SB, Osoegawa K, Schwartz DC, Shaw-Smith C, Stankiewicz P, Steward C, Swarbreck D, Venkataraman V, Whittaker CA, Yang X, Zimmer AR, Bradley A, Hubbard T, Birren BW, Rogers J, Lander ES, Nusbaum C. DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage. Nature. 2006 Apr 20;440(7087):1045-9. Abstract

Comments on Related News


Related News: Lis1 Acts as Middleman for Actin and Microtubules

Comment by:  Akira Sawa, SRF Advisor
Submitted 12 January 2006
Posted 12 January 2006

I found the paper by Kholmanskikh and colleagues, which proposes a novel role for LIS1 in neuronal motility by bridging calcium signaling to Cdc42, of great interest for schizophrenia research. LIS1 was originally identified as the causative gene for lissencephaly, but cascades that include LIS1 may have implications for schizophrenia. Several groups, including ours, have reported that a candidate gene product for schizophrenia, DISC1, forms a protein complex with LIS1 (Brandon et al., 2004; Kamiya et al., 2005).

My collaborators, Brian Kirkpatrick and Rosy Roberts, have observed and presented data that DISC1 immunoreactivity is enriched in some (but not all) of the postsynaptic densities, where Rho-family GTPases, such as Cdc42, also occur and regulate synaptic functions (Society for Neuroscience Meeting, 2004). Many of us agree that schizophrenia is, at least in part, a disorder of synapses. Taken all together, it may be useful to have a working hypothesis that a candidate susceptibility gene product for schizophrenia, DISC1, may have an additional role in regulating synaptic functions via Rho-family GTPases, probably in some association with LIS1.

This paper may attract researchers on schizophrenia in another context. The authors used D-serine as a trigger of calcium signaling via activation of the NMDA receptor. Although several genes coding for proteins that are involved in synthesis and degradation of D-serine have been associated with schizophrenia, pathophysiological roles for D-serine remain to be elucidated. In this sense, the impact of D-serine in activation of Cdc42 and synaptic morphology may have implications for schizophrenia research. Personally speaking, it is the most interesting point in this paper that the authors use D-serine in this type of experiment.

View all comments by Akira Sawa

Related News: CNP Findings Strengthen Oligodendrocyte Link to Schizophrenia

Comment by:  Hans W. Moises
Submitted 24 January 2006
Posted 24 January 2006
  I recommend the Primary Papers

This is another important study supporting the glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia we proposed in 2002 (Moises et al., 2002). The glial synaptic destabilization hypothesis is based on the landmark 1997 paper by Pfrieger and Barres and the tripartite synapse model suggested by Philip Haydon and coworkers (Araque et al., 1999; Pascual et al., 2005). In reference to its underlying principle, the glial growth factors deficiency and synaptic destabilization hypothesis might also more conveniently and briefly be designated as the weakened tripartite-synapse hypothesis of schizophrenia.

References:
Moises HW, Zoega T, Gottesman II. The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia. BMC Psychiatry. 2002;2:8. Abstract

Moises HW, Gottesman II. Does glial asthenia predispose to schizophrenia? Arch Gen Psychiatry 2004; 61:1170. Abstract

Pfrieger FW, Barres BA. Synaptic efficacy enhanced by glial cells in vitro. Science. 1997;277:1684-7. Abstract

Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 1999; 22:208-15. Abstract

Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, Takano H, Moss SJ, McCarthy K, Haydon PG. Astrocytic purinergic signaling coordinates synaptic networks. Science 2005; 310: 113-6. Abstract

View all comments by Hans W. Moises

Related News: CNP Findings Strengthen Oligodendrocyte Link to Schizophrenia

Comment by:  Daniel StewartKenneth Davis
Submitted 31 January 2006
Posted 31 January 2006

Peirce's paper is an exciting addition to the white matter hypothesis in schizophrenia. (Note: many of the authors of this paper are colleagues of ours at the Conte Center investigating white matter in schizophrenia at Mount Sinai.) As noted in the news story, findings from a number of different areas are beginning to come together in support of the white matter hypothesis in schizophrenia. Genetic findings in myelin-related genes, as outlined and referenced above, are demonstrating increased susceptibility to schizophrenia. Imaging findings from diffusion tensor studies are demonstrating abnormalities across multiple brain areas (reviewed in Kubicki et al., 2005), with more recent studies showing that specific white matter tracts are not only abnormal in schizophrenia, but are associated with symptomatology and cognitive deficits (Kubicki et al., 2002; Kubicki et al., 2003; Nestor et al., 2004). Postmortem examination is revealing that oligodendrocytes are decreased in number and abnormally spaced in patients with schizophrenia (Hof et al., 2002; Hof et al., 2003). These converging data argue strongly for the involvement of myelin, oligodendrocytes, and white matter in schizophrenia.

We continue to examine various aspects of white matter involvement in schizophrenia with the hope of providing both translational data (i.e., the relationship between symptom severity or independent living and white matter coherence) and further basic science data that may shed some light on upstream events that contribute to myelin and oligodendrocyte deficits. These new data by the Owen and O'Donovan group are a valuable contribution.

References:
Hof PR, Haroutunian V, Copland C, Davis KL, Buxbaum JD. Molecular and cellular evidence for an oligodendrocyte abnormality in schizophrenia. Neurochem Res. 2002 Oct;27(10):1193-200. Abstract

Hof PR, Haroutunian V, Friedrich VL Jr, Byne W, Buitron C, Perl DP, Davis KL. Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol Psychiatry. 2003 Jun 15;53(12):1075-85. Abstract

Kubicki M, McCarley R, Westin CF, Park HJ, Maier S, Kikinis R, Jolesz FA, Shenton ME. A review of diffusion tensor imaging studies in schizophrenia. J Psychiatr Res. 2005 Jul 13; [Epub ahead of print] Abstract

Kubicki M, Westin CF, Maier SE, Frumin M, Nestor PG, Salisbury DF, Kikinis R, Jolesz FA, McCarley RW, Shenton ME. Uncinate fasciculus findings in schizophrenia: a magnetic resonance diffusion tensor imaging study. Am J Psychiatry. 2002 May;159(5):813-20. Abstract

Kubicki M, Westin CF, Nestor PG, Wible CG, Frumin M, Maier SE, Kikinis R, Jolesz FA, McCarley RW, Shenton ME. Cingulate fasciculus integrity disruption in schizophrenia: a magnetic resonance diffusion tensor imaging study. Biol Psychiatry. 2003 Dec 1;54(11):1171-80. Erratum in: Biol Psychiatry. 2004 Mar 15;55(6):661. Abstract

Nestor PG, Kubicki M, Gurrera RJ, Niznikiewicz M, Frumin M, McCarley RW, Shenton ME. Neuropsychological correlates of diffusion tensor imaging in schizophrenia. Neuropsychology. 2004 Oct;18(4):629-37. Abstract

View all comments by Daniel Stewart
View all comments by Kenneth Davis

Related News: CNP Findings Strengthen Oligodendrocyte Link to Schizophrenia

Comment by:  William Honer
Submitted 4 March 2006
Posted 5 March 2006
  I recommend the Primary Papers

The Peirce et al. paper represents an important contribution to understanding the possible mechanisms through which genetic risk factors could contribute to the pathophysiology of schizophrenia. Studies of SNPs in candidate genes for schizophrenia are most clearly related to mechanism when the SNP changes amino acid sequence (rarely), or when the SNP changes mRNA expression (commonly postulated, but less often demonstrated). Studies combining SNP and mRNA analyses are challenging, and Peirce et al. provide a novel approach—by measuring the relative amount of mRNA expressed from the variant and the wild-type alleles in brain tissue from heterozygotes. They demonstrated relatively reduced expression from the variant allele. It must be noted however, that these studies were carried out in brain tissue from individuals described as being “free from psychiatric or neurological disorder at time of death” (not schizophrenia samples as suggested by the SRF news story [Editor's note: since corrected]), and the total expression of CNP mRNA was not determined. While CNP mRNA expression is reported to be lower in schizophrenia, and Peirce et al. demonstrate the variant allele is a risk factor for schizophrenia in studies of genetic association, it remains uncertain to what extent the lower CNP mRNA expression in schizophrenia is related to genetic variation or to other factors. CNP mRNA differences in expression between schizophrenia and control samples appear to be of different magnitude in different brain regions from the same cases (Katsel et al., 2005). This could represent non-genetic effects. However, genetic variation in CNP could also be more or less likely to be expressed in different brain regions. In this regard, the samples used in the Peirce et al. study were mixed, coming from frontal, parietal, or temporal cortex. Studies with larger sample sizes, and of schizophrenia as well as control tissues, will be needed to test these possibilities.

View all comments by William Honer