SCARB1 downregulation in adrenal insufficiency with Allgrove syndrome

• Published in: Orphanet journal of rare diseases Vol. 18; no. 1; p. 152
• Main Authors: Bitetto, Giacomo, Lopez, Gianluca, Ronchi, Dario, Pittaro, Alessandra, Melzi, Valentina, Peverelli, Erika, Cribiù, Fulvia Milena, Comi, Giacomo P, Mantovani, Giovanna, Di Fonzo, Alessio
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 19.06.2023; BioMed Central; BMC
• Subjects: AAAS gene; Achalasia; ACTH; Adrenal cortex; Adrenal glands; Adrenal insufficiency; Adrenal Insufficiency - genetics; Adrenal Insufficiency - metabolism; Adrenal Insufficiency - pathology; Adrenocorticotropic hormone; Allgrove syndrome; Analysis; Cholesterol; Corticosteroids; Cyclic adenylic acid; Down-regulation; Down-Regulation - genetics; Esophageal Achalasia - genetics; Esophageal Achalasia - metabolism; Esophageal Achalasia - pathology; Genetic aspects; Hormones; Humans; Kinases; Medical research; MicroRNA; MicroRNAs; Morphology; Mutation; Nerve Tissue Proteins - genetics; Nuclear Pore Complex Proteins - genetics; Nuclear Pore Complex Proteins - metabolism; Nuclear Proteins - genetics; PKA; Porins; Protein kinase A; Protein kinases; Proteins; Rare diseases; SCARB1; Scavenger receptors; Scavenger Receptors, Class B - genetics; Scavenger Receptors, Class B - metabolism; Steroids; Italy; Allgrove syndrome; SCARB1; Adrenal insufficiency; Adrenal cortex; PKA
• ISSN: 1750-1172; 1750-1172
• DOI: 10.1186/s13023-023-02763-w

Allgrove disease is a rare genetic syndrome characterized by adrenal insufficiency, alacrimia, achalasia and complex neurological involvement. Allgrove disease is due to recessive mutations in the AAAS gene, which encodes for the nucleoporin Aladin, implicated in the nucleocytoplasmic transport. The adrenal insufficiency has been suggested to rely on adrenal gland-ACTH resistance. However, the link between the molecular pathology affecting the nucleoporin Aladin and the glucocorticoid deficiency is still unknown. By analyzing postmortem patient's adrenal gland, we identified a downregulation of Aladin transcript and protein. We found a downregulation of Scavenger receptor class B-1 (SCARB1), a key component of the steroidogenic pathway, and SCARB1 regulatory miRNAs (mir125a, mir455) in patient's tissues. With the hypothesis of an impairment in the nucleocytoplasmic transport of the SCARB1 transcription enhancer cyclic AMP-dependent protein kinase (PKA), we detected a reduction of nuclear Phospho-PKA and a cytoplasmic mislocalization in patient's samples. These results shed a light on the possible mechanisms linking ACTH resistance, SCARB1 impairment, and defective nucleocytoplasmic transport.