Zinc finger protein 804A
|Zinc finger protein 804A|
Zinc finger protein 804A is a protein that in humans is encoded by the ZNF804A gene. The human gene maps to chromosome 2 q32.1 and consists of 4 exons that code for a protein of 1210 amino acids (137 kDa).
Little is known about the characteristics and function of the encoded protein. However, the protein sequence codes for a domain characteristic of a classical C2H2-type zinc finger near the N-terminal end.
Binding of DNA
The tertiary structure of the C2H2 finger consists of a beta hairpin folded against an alpha helix. The folding occurs via a zinc(II) ion that coordinates to two cysteine residues (one on each beta sheet) and two histidine residues (both on the α-helix). ZNF804A might use its zinc finger to bind DNA in a sequence-specific manner. For example, Carl Pabo and his colleagues in 1991 discovered that mouse transcription factor Zif268 binds DNA using three linked C2H2 zinc fingers. Amino acid residues sticking out from the α-helices of the zinc fingers interact with the guanine-rich region of the DNA double helix through hydrogen bonds and electrostatic and hydrophobic interactions. The spacing of the residues matches the spacing of the base pairs. Zinc fingers fit into the major groove and wrap around the DNA helix for almost one turn.
Association with Schizophrenia
What is Schizophrenia?
Schizophrenia is best described as a disorder in which a person’s ability to function normally is compromised by the inability to distinguish between what is real and what is not. The three main psychotic classes associated with schizophrenia are perceptual (visible), ideational (thoughts) and behavioural (actions). In the class of perceptual domain, hallucinations are the most common symptoms observed. Hallucinations can be plainly described as perceiving imaginary things as real, i.e. sensing things that are a creation of the individual’s mind. In the class of ideational domain, delusional disorder is the most common symptom observed. Delusional disorder results in the patient’s continued belief despite being continuously presented evidence against it. In the class of behavioral domain, patients experience several physical abnormalities, such as bizarre movements, postures and speech.
Schizophrenia has been viewed as a progressive disorder of the brain for over 90 years. The neuroimaging studies conducted by Lieberman et al. on schizophrenic patients of various backgrounds have confirmed several hypothesized structural brain abnormalities, along with the grey matter reduction and further observed reduction in size of hippocampus, thalamus, temporal lobe, and prefrontal cortex which are primarily soft tissue structures in the brain.
Clinical significance of ZNF804A
In humans, ZNF804A is expressed broadly throughout the brain, especially in the developing hippocampus and the cortex, as well as in the adult cerebellum. ZNF804A is expected to bind DNA and thus regulate gene expression like other zinc finger proteins. Interestingly, the mouse homologue of ZNF804A, zfp804a, has recently been reported as a target for HOXC8, suggesting that ZNF804A may be involved in the regulation of early neurodevelopment.
A Genome-wide association study (GWAS) has identified ZNF804A as a susceptibility gene for schizophrenia. From family, twin, and adoption studies, schizophrenia is found to have heritability of ~80% and it is suspected that risk results from multiple genetic variants of small effect. The single-nucleotide polymorphism (SNP) rs1344706 in intron 2 of ZNF804A has been identified as a variant that is most strongly associated with schizophrenia.
The same SNP has been reported to correlate with slightly disturbed functional coupling of several brain regions in healthy persons, resembling the changes described in schizophrenia. A further study revealed that the SNP rs1344706 was consistent with schizophrenia association in European patients, but not in Han Chinese patients. Moreover, the study showed that SNPs rs1021042 and rs359895 are associated with schizophrenia in Han Chinese patients, and that the rs359895 allele increases the promoter activity of ZNF804A. The results of another study suggest that there is no relationship between variant rs1344706 and impaired cognitive function in schizophrenia patients and the results of yet another study indicate that ZNF804A also plays a role in how schizophrenia symptoms respond to antipsychotics.
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