Overexpression of X Chromosome Genes Is Biomarker for Female Mental Disorders

A recent paper suggested that elevated expression of the genes XIST (X-inactive specific transcript) and KDM5C (lysine-specific demethylase 5C) could be used as a biological marker for diagnosis of major affective disorders in a significantly large subset of female patients from the general population.

Xist is an RNA gene on the X chromosome that acts as major effector of the X inactivation process. X-inactivation is a process by which one of the two copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by its being packaged in such a way that it has a transcriptionally inactive structure called heterochromatin. As nearly all female mammals have two X chromosomes, X-inactivation prevents them from having twice as many X chromosome gene products as males, who only possess a single copy of the X chromosome. The choice of which X chromosome will be inactivated is random, but once an X chromosome is inactivated it will remain inactive throughout the lifetime of the cell and its descendants in the organism.

Lysine-specific demethylase 5C is an enzyme that in humans is encoded by the KDM5C gene. The DNA-binding motifs suggest this protein is involved in the regulation of transcription and chromatin remodeling. Mutations in this gene have been associated with X-linked mental retardation.

Investigators at the University of California, San Diego (USA) studied expression of XIST and several X-linked genes in 36 lymphoblastoid cell lines from healthy females and 60 lymphoblastoid cell lines from female patients with either bipolar disorder or recurrent major depression. XIST and KDM5C expression was also quantified in 48 RNA samples from postmortem human brains of healthy female controls and female psychiatric patients.

Results revealed that the XIST gene was significantly over expressed in the lymphoblastoid cells of female patients with either bipolar disorder or major depression. The X-linked escapee gene KDM5C also displayed significant up-regulation in the patients' cells. Expression of XIST and KDM5C was highly correlated. Studies on human postmortem brains supported over-expression of the XIST gene in female psychiatric patients.

“There has been an utmost urgency to identify biomarkers for mental illness that could significantly impact research and drug development,” said senior author Dr. Xianjin Zhou, assistant professor of psychiatry at the University of California, San Diego. “Our results indicate that a large subpopulation of female psychiatric patients from the general population may have abnormal function of the inactive X chromosome. These results are powerful in that early diagnosis of mental illness could possibly happen with a simple blood test, leading to better interventions, therapy, and treatment options.”

The paper was published in the June 16, 2015, online edition of the journal EBioMedicine.

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