From β-Catenin to ARM-Repeat Proteins in Adrenocortical Disorders

Abstract

Armadillo-containing proteins (ACPs) are a large family of evolutionary conserved proteins, characterized by the tandem repeat copy of a 42 amino acids motif, which forms a 3 dimensional protein-protein interaction domain. This permits ACPs to interact with plenty of partners and consequently, most of these proteins have several independent cellular roles. Perhaps the most well-known protein of this family is β-catenin, which is crucial in the regulation of development and adult tissue homeostasis through its 2 independent functions, acting in cellular adhesion in addition to being a transcriptional co-activator. APCs have important functions in many tissues, but here we summarize the adrenocortical role of 2 well-described ACPs, β-catenin (CTNNB1), Adenomatous Polyposis Coli (APC), and discuss the possible role in the adrenal cortex of the most recently discovered, Armadillo-repeat containing 5 (ARMC5).

Primary Aldosteronism andARMC5Variants

“…Our group and others previously described ARMC5 inactivating mutations as a frequent cause of macronodular adrenal hyperplasia and Cushing syndrome (25)(26)(27)(28)(29). In the present study, we also identified predicted damaging germline ARMC5 gene mutations in 10.7% of patients with PA (six of 56 patients).…”

“…We and others recently described germline and somatic mutations in an armadillo repeat containing 5 (ARMC5) gene that causes hypercortisolism in primary macronodular adrenal hyperplasia (PMAH) (25)(26)(27)(28)(29). ARMC5 maps to 16p11.2 and is likely to be a tumor-suppressor gene (27). Tumors caused by mutations in ARMC5 are likely to be polyclonal: both alleles of ARMC5 carry mutations at the somatic and germline levels.…”

Somatic and inherited mutations in primary aldosteronism

“…Activation of Wnt/β-catenin pathway is one of the major features in APA, being found in at least two-thirds of APA (Boulkroun et al 2011, Berthon et al 2012, Berthon & Stratakis 2014. The Wnt/β-catenin pathway plays an important role in embryonic development, stem cell maintenance and differentiation in many tissues, especially normal adrenal development and tumorigenesis (El Wakil & Lalli 2011).…”

“…ARMC5 belongs to the large family of armadillo (ARM)-repeat-containing proteins, of which the best-known member is β-catenin and is likely to be a tumor-suppressor gene (Berthon & Stratakis 2014). ARMC5 inactivation appears to affect steroidogenesis.…”

Genetics of primary macronodular adrenal hyperplasia

“…However the function of ARMC5 remains unknown as do the mechanisms of the inactivating mutations of ARMC5 involved in development of adrenal macronodular hyperplasia (Berthon & Stratakis 2014).…”