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

Endocrine Abstracts (2005) 9 OC26

Identification of a defective gene in Familial Glucocorticoid Deficiency type 2 as a ACTH receptor accessory factor responsible for cell surface trafficking

LA Metherell1, JP Chapple2, S Cooray1, D Naville3, M Begeot3, A Huebner4, ME Cheetham2 & AJL Clark1

1Molecular Endocrinology Centre, WHRI, London, UK; 2Division of Pathology, Institute of Ophthalmology, UCL, London, UK; 3INSERM-INRA, U418, Lyon, France; 4Department of Paediatrics, Technical University of Dresden, Germany.

FGD is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex to stimulate glucocorticoid production. The disease is caused by mutations in ACTHR or MC2R in 25% of cases, termed FGD type 1, and has previously been linked to a locus on chromosome 8q12.2-21.2 in a single family with FGD type 2. We have recently described a novel gene (FGD2) that when defective is a second cause of FGD. Sequencing of this gene in 100 FGD2 patients has lead to the discovery of 7 mutations (M1I, IVS1ds+1 G to T, IVS1ds+1 G to C, IVS1ds+1 G to A, IVS1ds+1 del G and IVS1ds+3 insT and V44X) in 21 families involving 25 patients in all.

Given the similarities in phenotype resulting from MC2R or FGD2 mutations and their co-expression in the adrenal cortex we reasoned that FGD2 might be an accessory factor that is necessary for correct functioning of MC2R. FGD2 was shown to colocalise with MC2R both at the endoplasmic reticulum and plasma membrane in CHO and SKNSH cells. If MC2R is transfected it remains intracellular but with the addition of FGD2 it is trafficked to the cell surface. Reciprocal co-IP was employed to demonstrate the formation of a complex between FGD2 and MC2R. This interaction allows the formation of a fully functional MC2R in SKNSH cells since transfection of either MC2R or FGD2 alone does not increase the cells responsiveness to ACTH stimulation, but if the two are co-transfected there is a marked increase in cAMP response to ACTH.

In conclusion the gene encodes a protein that is intimately involved in the production of a functioning MC2R and it achieves this either by acting to traffic the MC2R across the ER and to the cell surface and/or by enabling correct protein folding.

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