Albany 2015:Book of Abstracts

Albany 2015
Conversation 19
June 9-13 2015
©Adenine Press (2012)

Do large Purine repeat sequences play a role in transcriptional regulation of genes associated with neurological disorders?

Purine repeat sequences present in genome are known to act as hotspots for mutations leading to chromosomal imbalances. It is established that large purine repeats (PRs) form stable DNA triplex structure which can inhibit the gene expression. Friedreich's ataxia (FRDA), the autosomal neurodegenerative disorder is the only human disease known so far, where large purine (GAA) repeat in FXN gene is known to inhibit the expression of frataxin protein. Considering the above facts, we explored the hidden purine repeats (PRn with n ≥ 200) if any, in the human genome. The results showed 28 PRs, which are mostly restricted to the intronic regions. Interestingly, the transcriptome expression analysis of PR-carrying genes revealed that most of them are down-regulated in neurological disorders (Autism, Alzheimer's disease, schizophrenia, epilepsy, mental retardation, Parkinson's disease, brain tumor) as compared to that in healthy controls. The altered gene expression in brain disorders can be interpreted due to a possible expansion of purine repeats leading to formation of very stable DNA-triplex and/or alleviation of the repair enzymes and/or other unknown cellular factors in brain disorders. Interactome analysis identified four PR-genes in signaling pathways whose dysregulation is correlated directly with pathogenesis: GRK5 in Alzheimer�s disease; FGF14 in craniosynostosis, mental retardation and FLT1 in neuroferritinopathy. By virtue of being mutational hotspots and their ability to form DNA-triplex, the purine repeats in genome disturb the genome integrity and interfere with the transcriptional regulation. However, validation of the disease linkage of PR-genes can be validated using gene knock-out techniques.

Himanshu N. Singh
Moganty R. Rajeswari*

Department of Biochemistry
All India Institute of Medical Sciences
New Delhi-110029, India

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