A threonine to isoleucine missense mutation in the pericentriolar material 1 gene is strongly associated with schizophrenia.

Markers at the pericentriolar material 1 gene (PCM1) have shown genetic association with schizophrenia in both a University College London (UCL) and a USA-based case-control sample. In this paper we report a statistically significant replication of the PCM1 association in a large Scottish case-control sample from Aberdeen. Resequencing of the genomic DNA from research volunteers who had inherited haplotypes associated with schizophrenia showed a threonine to isoleucine missense mutation in exon 24 which was likely to change the structure and function of PCM1 (rs370429). This mutation was found only as a heterozygote in 98 schizophrenic research subjects and controls out of 2246 case and control research subjects. Among the 98 carriers of rs370429, 67 were affected with schizophrenia. The same alleles and haplotypes were associated with schizophrenia in both the 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. Genotyping of the new variants discovered in the UCL case-control sample strengthened the evidence for allelic and haplotypic association (P=0.02-0.0002). Given the number and identity of the haplotypes associated with schizophrenia, further aetiological base pair changes must exist within and around the PCM1 gene. PCM1 protein has been shown to interact directly with the disrupted-in-schizophrenia 1 (DISC1) protein, Bardet-Biedl syndrome 4, and Huntingtin-associated protein 1, and is important in neuronal cell growth. In a separate study we found that clozapine but not haloperidol downregulated PCM1 expression in the mouse brain. We hypothesize that mutant PCM1 may be responsible for causing a subtype of schizophrenia through abnormal cell division and abnormal regeneration in dividing cells in the central nervous system. This is supported by our previous finding of orbitofrontal volumetric deficits in PCM1-associated schizophrenia patients as opposed to temporal pole deficits in non-PCM1-associated schizophrenia patients. Caution needs to be exercised in interpreting the actual biological effects of the mutations we have found without further cell biology. However, the DNA changes we have found deserve widespread genotyping in multiple case-control populations.

Identification of a calcium-inducible, cyclosporine sensitive element in the IFN-gamma promoter that is a potential NFAT binding site.

Cyclosporine (CsA) inhibits cytokine transcription by preventing the activation of key promoter sites, in particular the binding of nuclear factor of activated T cells (NFAT) to the IL-2 NFAT site and the "P" site in IL-4. To identify potential NFAT-like sites in the IFN-gamma promoter, we sought areas of homology with the known sites in other promoters. In the promoter region of the mouse and human IFN-gamma gene, we identified two repeats of a consensus sequence ATTTCCnnT, designated P1 and P2 because of their homology to the calcium-inducible and CsA-sensitive "P" sequences in the IL-4 promoter. In electrophoretic mobility shift assay (EMSA), a probe containing the second P sequence "P2" in the human IFN-gamma gene bound nuclear proteins from stimulated, but not unstimulated, humans T cells. The cytosol of unstimulated cells contained similar binding activity that decreased after stimulation, indicating that this binding activity translocated to the nucleus after stimulation. CsA inhibited nuclear translocation. Competition studies demonstrated that oligomers containing the sequences P1 and P2 in IFN-gamma gene, the NFAT site in the IL-2 gene, and the IL-4 P site competed with the P2 probe for protein binding, whereas an oligomer containing mutations in the P2 site did not. Addition of anti-NFAT antiserum altered protein binding to P2, indicating that the proteins were either identical or related to NFAT. Stimulation of T cells transfected with constructs containing three copies of the P2 sequence enhanced CAT activity in response to ionomycin, and this effect was blocked by CsA. These results suggest that the P2 sequence, and probably the P1 sequence, in the IFN-gamma promoter are NFAT binding sites and contribute to the calcium inducibility and CsA sensitivity of IFN-gamma production.

Detecting the dangerous, violent or criminal patient: an analysis of referrals to maximum security psychiatric care.

Britain's high security hospitals provide care for mentally disordered patients who have dangerous, violent or criminal propensities. The State Hospital, Carstairs, takes referrals from the population of Scotland and Northern Ireland. This retrospective case-control study describes the sociodemographic and clinical characteristics of referrals (n=149) to the State Hospital during a 12-month period, and delineates differences between admitted (n=57) and rejected (n=92) patients. The referrals had an average age of 31.1 years, and were mostly male (86.6%), single (64.4%) and unemployed (90.6%). Admitted patients were more likely to have a criminal history, to be psychotic, to have a family history of mental disorder and to be viewed by the assessor as having psychotic beliefs which contributed to the behaviour or alleged offence leading to the referral. Rejected patients were more likely to have been remanded to prison or assessed by specialist registrars. Patients admitted to high security psychiatric care are more likely to show dangerous behaviour secondary to psychosis. These findings are in keeping with the requirements of mental health legislation and the admissions policy.