Laboratory of Rosario Perona Abellón

Research topics

Diagnosis and new therapies in dyskeratosis congenita and pulmonary fibrosis

The group has been focussed in the last years in the study of telomeres and telomere-related diseases. Telomeres are nucleo-protein complexes at the terminal end of the chromosomes and protect them from degradation. The human telomere sequence consists in tandem repetitions of the AATGGG sequence that is recognized by a protein complex named shelterin to form a stable heterochromatin structure. Placed at the end of a lineal DNA molecule, telomeres cannot be completely replicated by DNA polymerases and that results in shortening in every replication cycle. This process is prevented by the activity of the telomerase complex that elongates telomeres in embryonic, germinal and tissue stem cells. In most cells of somatic tissues telomerase activity is not expressed and their telomeres are shortened with the aging of the individual. Excessively short telomeres produce cell-cycle arrest, senescence or apoptosis that is one of the causes of aging. 

There are a number of rare diseases that are being studied by our group, including dyskeratosis congenita, aplastic anemia and pulmonary fibrosis that harbour mutations in genes coding for components of the telomerase, shelterin complexes and auxiliary proteins. Shortening of telomeres is also observed in related diseases such as Ataxia telangiectasia. 

Our research is focussed in the following topics:

1. GSE4 as possible therapeutic molecule. Our group has described that a dyskerin-derived peptide (GSE4) has a potentially therapeutic effect on telomere-related diseases. Expression of this peptide increases telomerase activity and cell proliferation in cells isolated from patients of dyskeratosis congenita and Ataxia telangiectasia. In addition, oxidative stress and DNA damage is prevented by the expression of the peptide that has been designed as orphan drug for treatment of dyskeratosis congenita. The mechanism of action of GSE4 and the possible therapeutic effects in these and other telomere-related diseases are presently being studied.

2. Diagnosis of telomere-related diseases. We are collaborating with several hospitals in the diagnosis of telomere-related diseases that are very difficult to diagnose based exclusively on clinical criteria. Telomere length is first determined since patients affected by these diseases have very short telomeres, below the 10% and frequently below the 1% of the control population.  Once diagnosed, the molecular cause of the disease is studied by determining possible pathological variants in the genes coding for proteins involved in telomere homeostasis. Massive sequencing of a panel of related genes and exome sequencing are used in these studies. Finally, we perform in vitro studies to determine the functional relevance of the possibly pathogenic variants.