SCARB1 downregulation in adrenal insufficiency with Allgrove syndrome

BackgroundAllgrove 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.ResultsBy 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.ConclusionsThese results shed a light on the possible mechanisms linking ACTH resistance, SCARB1 impairment, and defective nucleocytoplasmic transport.

Automated summary

Allgrove disease is a rare genetic syndrome characterized by multiple symptoms. The study found downregulation of Aladin transcript and protein, as well as impairment in the nucleocytoplasmic transport. These findings suggest a potential link between ACTH resistance, SCARB1 impairment, and defective nucleocytoplasmic transport.