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PCM1 Gene Is Linked to Altered Brain Morphology in Schizophrenia

17 August 2006. The case for subtyping schizophrenia by genetic study receives support in a paper published in the August issue of the Archives of General Psychiatry. Hugh Gurling of University College London and his multi-institution team found that variations in the gene for pericentriolar material 1 (PCM1) on chromosome 8 are associated with risk of schizophrenia. The researchers also provide imaging evidence that having these schizophrenia-associated variations in PCM1 leads to a different pattern of brain abnormality than is seen in other cases of schizophrenia.

Hunting for genes of small effect
Linkage studies of schizophrenia have pointed to a number of different loci on different chromosomes as being involved in the disorder, and meta-analyses suggest that the inconsistencies reflect heterogeneity of susceptibility genes acting in different individuals and families (see, e.g., Lewis et al., 2003). Similarly, association studies have not consistently replicated the involvement of individual genes. The conclusion geneticists have been able to draw from these findings is that there are going to be several different modes of transmission for different subtypes of schizophrenia.

Chromosome 8 seems to be a particularly good hunting ground for genes involved in schizophrenia. Several regions of the chromosome have been implicated (see, most recently, Walss-Bass et al., 2006), and neuregulin 1 (NRG1), one of the genes of most interest (see SRF related news story), is located in the same region of the chromosome as PCM1 (8p21-22). Also in this region are PPP3CC (calcineurin), DRP2 (dihydropyrimidinase-related protein 2), and FZD3 (frizzled), all of which have been linked to increased likelihood of having schizophrenia.

In their current study, Gurling’s team first revisited their earlier genomewide scan of 13 families with multiple cases of schizophrenia, which had found linkage to 8p21-22 (Gurling et al., 2001). Reanalyzing the data, the researchers found that variation at the microsatellite marker D8S261, located within the PCM1 gene, was associated with schizophrenia. They replicated the association with D8S261 in a case-control sample of 450 patients and 450 controls from London and surroundings, along with statistically significant association between schizophrenia and an additional microsatellite marker and several single nucleotide polymorphism (SNP) markers within the gene. Furthermore, several haplotypes consisting of three or four of these markers showed strongly significant associations with schizophrenia.

Interestingly, the researchers also found an association between the NRG1 gene and schizophrenia in this sample, but the evidence was not as strong as that seen for PCM1. They also report that they found no evidence for susceptibility from the PPP3CC or FZD3 genes.

The researchers went on to confirm the association of D8S261 variation with schizophrenia in a separate U.S. population of 100 schizophrenia and schizoaffective disorder patients and their parents, but they failed to replicate the results in a Scottish case-control sample of 200 cases and 200 controls.

Imaging “PCM1 schizophrenia”
Just what is this PCM1, and how might variations in the gene contribute to schizophrenia? The protein product is a player at the centrosome, the organizing hub of microtubules, meaning that it can assist in, or disrupt, a range of cellular processes from cell division and migration to axonal transport to synaptic function. PCM1 has been known to associate with other molecules that have been investigated in schizophrenia, including Nudel and Lis1 (see Guo et al., 2006), which of course makes it tempting to speculate that it might have ties to DISC1 (see SRF related news story).

In the second phase of the study, Gurling and colleagues chose to look for gross anatomical brain effects of PCM1 genetic variation, using voxel morphometry MRI. They selected two genetically distinct schizophrenia subgroups from the London case-control study for structural imaging: one group whose PCM1 genes harbored two of the schizophrenia-associated microsatellite or SNP marker variants (termed the SZ8 group; n = 14) and another group that displayed none of the marker alleles associated with schizophrenia (SZ0; n = 13).

Consistent with many previous studies, both patient groups showed significant reductions in gray matter compared to controls, both in absolute terms and relative to white matter, but no differences in white matter volume. The two schizophrenia groups also did not differ from each other on these global measures. However, there were clear regional differences. The SZ8 group had significantly lower gray matter volume, relative to controls, in the orbitofrontal cortex, bilaterally. By contrast, the SZ0 group did not differ from controls in this region, but showed lower gray matter volumes in a number of other brain areas.

When the two schizophrenia groups were compared directly, medial orbitofrontal cortex had significantly lower volume in SZ8 versus SZ0 patients. Conversely, left hippocampus, right dorsolateral prefrontal cortex, and the temporal poles of both hemispheres, were reduced in volume in SZ0 versus SZ8 patients.

The pattern of morphologic differences led the authors to speculate that it might be possible to distinguish PCM1-associated schizophrenia from the remainder of patients diagnosed with schizophrenia. For example, orbitofrontal cortex is known to be critical for reward-related or motivational processing. Deficits in these domains might contribute to the constellation of deficits (including greater affective and cognitive deficits, along with poorer outcome) found with greater frequency in families with linkage to 8p21-22, compared to families with linkage to other chromosomal loci (Kendler et al., 2000). But, as the authors point out, the association of PCM1 with schizophrenia needs confirmation in other samples.—Hakon Heimer.

Gurling HM, Critchley H, Datta SR, McQuillin A, Blaveri E, Thirumalai S, Pimm J, Krasucki R, Kalsi G, Quested D, Lawrence J, Bass N, Choudhury K, Puri V, O'Daly O, Curtis D, Blackwood D, Muir W, Malhotra AK, Buchanan RW, Good CD, Frackowiak RS, Dolan RJ. Genetic association and brain morphology studies and the chromosome 8p22 pericentriolar material 1 (PCM1) gene in susceptibility to schizophrenia. Arch Gen Psychiatry. 2006 Aug;63(8):844-54. Abstract

Comments on News and Primary Papers
Comment by:  Akira Sawa, SRF Advisor
Submitted 22 August 2006 Posted 22 August 2006

Many linkage analyses have reproducibly reported 8p21-22 as a linkage hot locus for schizophrenia. The gene coding for neuregulin-1 is regarded as a factor that contributes to the linkage peak, but other genes may also be involved. Dr. Gurling and colleagues have conducted an excellent association study and obtained evidence that the gene coding for pericentriolar material 1 (PCM1) is associated with schizophrenia.

The results from the genetic portions of this are consistent with our unpublished biological study. (The abstract of Kamiya et al. has been submitted to SFN meeting at Atlanta in October 2006.) In exploring protein interactors of disrupted-in-schizophrenia-1 (DISC1), a promising risk factor for schizophrenia and bipolar disorder, we already came across PCM1 as a potential protein interactor of DISC1. This interaction has been confirmed by yeast two-hybrid and biochemical methods. In immunofluorescent cell staining, a pool of DISC1 and PCM1 are co-stained at the centrosome. Therefore, this genetic study is really encouraging us to move beyond our preliminary...  Read more

View all comments by Akira Sawa

Comment by:  Mary Reid
Submitted 20 August 2006 Posted 23 August 2006

Regarding the possibility that PCM1 may have ties to DISC1, it's of interest that when PCM1 function is inhibited there is reduced targeting of centrin, pericentrin and ninein to the centrosome (1). Miyoshi and colleagues (2) report that their data indicate that DISC1 localizes to the centrosome by binding to kendrin/pericentrinB. Might there be a failure of DISC1 to localize in the centrosome in PCM1 deficiency?

Do these families with PCM1-associated schizophrenia also have a history of scleroderma? It is also of interest that PCM1 is an autoantigen target in scleroderma (3), and there is a report of cerebral involvement of scleroderma presenting as schizophrenia-like psychosis (4).

Abelson Helper Integration Site 1 (AHI1) gene is a candidate gene for schizophrenia and mutations in AHI1 underlie the autosomal recessive Joubert Syndrome in which cerebellar vermis hypoplasia is reported.(5) Increased cerebellar vermis white-matter volume has recently been reported in males with schizophrenia.(6)

It's interesting that mutations in the centrosomal protein...  Read more

View all comments by Mary Reid

Comment by:  Mary Reid
Submitted 10 September 2006 Posted 12 September 2006

Den Hollander and colleagues (1) report that mutations in CEP290-nephrocystin-6 are a frequent cause of Leber's Congenital Amaurosis (LCA). Autistic signs are reported in both Joubert syndrome and LCA (2,3). Perhaps asparagine may be useful for those with LCA and dysmyelination.


1. den Hollander AI, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, Zonneveld MN, Strom TM, Meitinger T, Brunner HG, Hoyng CB, van den Born LI, Rohrschneider K, Cremers FP. Mutations in the CEP290 (NPHP6) Gene Are a Frequent Cause of Leber Congenital Amaurosis. Am J Hum Genet. 2006 Sep;79(3):556-61. Epub 2006 Jul 11. Abstract

2. Curless RG, Flynn JT, Olsen KR, Post MJ. Leber congenital amaurosis in siblings with diffuse dysmyelination. Pediatr Neurol. 1991 May-Jun;7(3):223-5. Abstract

3. Rogers SJ, Newhart-Larson S. Characteristics of infantile autism in five children with Leber's congenital amaurosis. Dev Med Child Neurol. 1989 Oct;31(5):598-608. Abstract

View all comments by Mary Reid

Comment by:  Mary Reid
Submitted 25 September 2006 Posted 28 September 2006

The asparagine synthetase gene has been mapped to 7q21.3 (1). Childhood-onset schizophrenia/autistic disorder has been described in a child with a translocation breakpoint at 7q21. Of further interest is that alcohol/drug abuse, severe impulsivity, paranoid personality, and language delay have been reported in other family members carrying this translocation.

Maybe the increased risk of schizophrenia following famine may be explained by the fact that starvation induces expression of ATF4 and asparagine synthetase. Is there an increased risk of mutation in these genes as a long-term response to famine?


1. Heng HH, Shi XM, Scherer SW, Andrulis IL, Tsui LC. Refined localization of the asparagine synthetase gene (ASNS) to chromosome 7, region q21.3, and characterization of the somatic cell hybrid line 4AF/106/KO15. Cytogenet Cell Genet. 1994;66(2):135-8. Abstract

2. Yan WL, Guan XY, Green ED, Nicolson R, Yap TK, Zhang J, Jacobsen LK, Krasnewich DM, Kumra S, Lenane MC, Gochman P, Damschroder-Williams PJ, Esterling LE, Long RT, Martin BM, Sidransky E, Rapoport JL, Ginns EI. Childhood-onset schizophrenia/autistic disorder and t(1;7) reciprocal translocation: identification of a BAC contig spanning the translocation breakpoint at 7q21. Am J Med Genet. 2000 Dec 4;96(6):749-53. Abstract

View all comments by Mary Reid

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