ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2007) 13 S8

Failing to stop, failing to signal, no insurance, and other trafficking defects in the adrenal

Adrian Clark

Barts & the London, QMUL, London, United Kingdom.

It is a widely held view that genetic mutations cause diseases by interfering with the normal function of the protein encoded by the gene in question, and there are many examples of this phenomenon. However it is increasingly apparent that in some cases mutant proteins have altered function because they have failed to assemble correctly, or because they fail to reach the correct compartment of the cell correctly. Recent work investigating certain inherited disorders of the adrenal cortex provides several illustrations of this view. ACTH is the principal stimulator of adrenal steroidogenesis and acts through a membrane receptor, the ACTH receptor. This receptor has an innate difficulty in locating itself at the plasma membrane. Certain ‘inactivating’ mutations of this receptor cause ACTH insensitivity and probably interfere primarily with the trafficking process, raising the possibility that appropriate pharmacological manipulation may overcome this defect. The machinery for trafficking this receptor is dependent on a specific requirement for a small accessory protein, the melanocortin 2 receptor accessory protein (MRAP). Nonsense mutations in MRAP lead to a second form of inherited ACTH insensitivity. The Triple A syndrome is a further inherited disease that often presents with ACTH insensitivity and is the result of mutations in a gene encoding a protein known as ALADIN. ALADIN is a component of the nuclear pore, but its specific function is unknown. Many mutations in ALADIN cause it to mis-localise to the nuclear membrane. Our data suggests that ALADIN functions as a transporter for Ferritin Heavy chain (FHC) into the nucleus. FHC has an under-recognised role in protecting the genome against free radical damage from reactive oxygen species, and this provides a credible pathogenic mechanism for this syndrome. This opens the possibility of limiting disease progression in this syndrome by the use of antioxidant therapy.

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