Development, Microenvironment and genetic alterations in adrenal and bone lesions of Carney complex – DevMiCar

Carney complex (CNC) is a rare genetic disease responsible for bone tumors (osteochondromyxomas, OCM) and hypersecreting adrenal lesions (primary pigmented nodular adrenocortical disease, PPNAD) causing pituitary-independent Cushing's syndrome (hypercortisolism). PRKAR1A, the main gene mutated in CNC, encodes the R1a regulatory subunit of PKA. By collecting a unique worldwide CNC cohort and developing mouse models with general haploinsufficiency (Prkar1a+/-) and adrenal-specific R1a ablation (AdKO), we have shown that RIa is a tumor suppressor whose loss induces expansion and sometimes reprogramming of pluripotent fetal cells within adult tissues. These findings qualified CNC as a disease that possibly affects progenitor cells. Our project is now to 1) demonstrate the progenitor origin of lesions using lineage tracing studies in mice; 2) assess the contribution of PKA catalytic subunits and microenvironment in pathogenesis; 3) identify new pathogenic mechanisms by expressing truncated R1a mutants found in severe forms in transgenic knock-in mice and by whole genome sequencing of patients lacking defects in CNC genes. This project should provide novel insights into stem/progenitor biology of the adrenal and bone and in-depth understanding of diseases associated with unbalanced PKA signaling, as well as provide possible molecular therapeutic targets for patients with bone and endocrine (adrenal) tumors.