Review Of Evidence That The Gene Encoding Zdhhc8 Contributes To The Risk Of Schizophrenia. Mukai, J Et Al. Proc. Natl. Acad. Sci. Usa

1891 words - 8 pages

BACKGROUND:The brain and nervous system is very complicated the knowledge of how it works and functions to make animals think, behave and act is growing. Schizophrenia is a chronic and disabling psychosis - a disorder of thought and sense of self that affects the brain and nervous system. Patients may suffer from impairment of cognitive function, but schizophrenia is distinguished from other dementias where cognitive disturbance is primary. Numerous different genetic susceptibility points for schizophrenia have been found for this disease like 6p22.3 (Straub et al. 2002). A susceptibility point for schizophrenia was found on chromosome 22q11 (Karayiorgou, M et al. 1995) and there have been many susceptibility points on this chromosome where mutations could occur such as PRODH (Liu, H. et al. 2002), COMT (Aleman, A. et al. 2003) and ZDHHC8 (Liu, H. et al. 2002). The function of ZDHHC8 is still not known but there is some suspicion that it plays a role at the synapse and in glutamatergic transmission. There are also other proteins that play a part in glutamatergic transmission that when not expressed properly could be a potential susceptibility point for schizophrenia. It is predicted that the expressed ZDHHC8 has four transmembrane domains. It also has a cysteine-rich domain including a Cys4 zinc finger-like metal binding site. Previous research and knowledge has brought the researchers to create this study to show a stronger link between ZDHHC8 on 22q11 as a susceptibility point for schizophrenia.AIMS:This study was performed to show that SNP rs175174 regulates the level of fully functional transcript by modulating the retention of intron 4 in the gene ZDHHC8 showing susceptibility to schizophrenia.RESULTS:To accomplish the goals set out by the experimenter this study had to be done in two parts. The first part constitutes the investigation into the effect of the rs175174 genotype on splicing intron 4 out of the ZDHHC8 gene. The second part looked at the effects on mice with the expression of the "risk" allele and "non-risk" allele in the brain. These combined experiments show how the retention of intron 4 within the expression of ZDHHC8 can lead to schizophrenia.The result from the analysis of the retention of intron 4 was found both in vivo and in vitro. The in vitro experiment showed that the RNA taken from human lymphocytes and subjected to reverse transcriptase, PCR amplification and sequencing showed two main products. These two products came from both the fully spliced form and the unspliced form retaining intron 4. The sequence analysis showed that the affected splicing site was at SNP rs175174 located in intron 4. The retention of intron 4 introduces a stop codon into the open reading frame leading to a shortening of translation. The in vivo experiment consisted of constructed minigenes for the "risk" and "nonrisk" alleles that were transfected into human embryonic kidney cells (HEK293). PCR amplification showed that these transfected...

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