Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between European scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other.

Genomics of cAMP signaling alterations in adrenal Cushing

Project Coordinator



Felix Beuschlein Universitätsklinik München Munich, Germany
Martin Fassnacht University Hospital Würzburg Würzburg, Germany
Anna Spada Fondazione IRCCS Milan, Italy

ACTH-independent Cushing’s syndrome (AICS) is a very rare condition (< 0.6/million/yr) due to primary adrenal cortex dysfunction that causes chronic cortisol excess leading to significant morbidity and mortality. AICS can be due to bilateral or unilateral adrenocortical dysfunction. For bilateral diseases in a subset of patients germline mutations of different cAMP pathway genes have been identified, while the cause of unilateral disease is largely unknown. The project aims using genomics (snp, transcriptome, next generation sequencing) to identify new genes in AICS. We have very recently identified by pilot exome and whole genome sequencing studies 2 genes involved in unilateral AICS and macronodular adrenal hyperplasia, respectively. One of these genes is known to be a component of the cAMP pathway and the other is not fully characterized yet but controls steroidogenesis. The proposed multicentre approach will enlarge the cohort of patients to determine the frequency of the discovered genetic alterations, analyze the genotype/phenotype correlation and identify new genes. Downstream targets of the mutated genes will be screened by transcriptome analysis. In vitro studies will investigate the effects of these alterations on cAMP signalling, steroidogenesis and adrenal cell survival. These approaches combining molecular tools in unique cohorts of patients with this rare condition and in vitro studies is expected to give innovative insights on the mechanisms of cortisol synthesis dysregulation, thereby, opening new perspective for early diagnosis and treatment.

E-Rare 2012 - Created by Toussaint Biger