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New insights on Aicardi-Goutieres Syndrome, a novel connection with DNA repair

19th national competition for scientific and technical research

Rare diseases

Senior Researcher : Pablo Huertas Sánchez

Research Centre or Institution : Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER)


Aicard-Goutières Syndrome (AGS) is a severe rare hereditary disease. It causes a progressive neurodegeneration that strongly compromises the survival of the patients. Indeed, over 80% of people diagnosed with AGS die less than decade after birth. It is a monogenic autosomic disorder, but of heterogenic etiology. In fact, there are 7 known genes which mutations can cause AGS. At the molecular level, AGS is believed to be dependent on an interferon-mediated autoimmune response towards specific aberrant nucleic acid structures that accumulate on those individuals bearing AGS mutations. Prior the initiation of this project, it was shown that one of the genes related to AGS, SAMHD1, is also directly involved in the repair of DNA breaks and stalled replication forks through homologous recombination. Additionally, we observed similar phenotypes with ADAR1. 

Thus, we proposed to study the connection between AGS-causing mutations and the repair of DNA breaks and stalled forks. So far, we have shown that not only all AGS-related mutations impair DNA repair, but also that such defect is mediated by an aberrant elimination of DNA:RNA hybrids, that act as roadblock for the repair machinery. Furthermore, we have seen that different treatments that were proposed to reduce interferon on those patients were able to rescue the defective DNA repair at the cellular level. Finally, we have taken the inverse approach and search for drugs that rescue the hampered DNA repair in patients-derived cells. Currently, we are analyzing if those drugs are also able to reduce the cellular interferon levels in AGS cellular models, thus suggesting they can be used as palliative treatments in the patients.


Scientific Production
Magazine Articles 1
Communications at national conferences 1
Communications at international conferences -


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