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Correlation between genotype, and telomere length, and phenotype in telomeropathies

Abstract

Telomeres are ribonuclear structures located at the ends of linear cromosomes that maintain genomic integrity. Germline mutations in genes involved in telomere repair and maintenance lead to excessive telomere shortening, ultimately resulting in cell senescence and/or apoptosis. In humans, telomere dysfunction manifests as disease compromising several organs, such as aplastic anemia (AA), disceratosis congenita (DC), pulmonary fibrosis (PF), hepatic cirrhosis, and a proclivity for cancer development. Collectively, these disorders are classified as telomeropathies. As the clinical presentations is heterogenous and the genetic basis is diverse, involving multiple inheritance patterns, it is necessary to understand the genotype-phenotype correlation in order to parse the cellular and molecular pathways involved in disease development, as well as to determine the effects of genotype on treatment response. The first objective of this project is to identify mutations in a panel of telomere-biology genes by next generation sequencing (NGS) in patients with telomeropathies in order to establish a correlation between. In addition, genotype, telomere length, phenotype, and response to treatment. In addition, we will evaluate the expression of RecQ helicases and TERRA (Telomeric-Repeat-Containing RNA), which may serve as molecular pathways for disease development, in patients' samples in order to identify potential modulators of replication, DNA repair, telomere integrity/maintenance, and telomerase activity. Potential abnormalities in RecQ helicases or TERRA, tentatively caused by genetic or epigenetic variations, will be determined for the first time in telomere diseases. The present project may help to elucidate the genetic and molecular bases of telomere disease clinical phenotype, response to therapy, and clinical outcome, bridging the gap between clinical research and molecular biology, dissecting the molecular mechanisms of disease, and potentially identify novel therapeutic targets. (AU)

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