title: ACTH resistance: genes and mechanisms.
abstract: ACTH resistance is a rare disorder typified by familial glucocorticoid deficiency (FGD), a genetically heterogeneous disease. Previously, genetic defects in FGD have been identified in the ACTH receptor gene (MC2R), its accessory protein (MRAP) and the steroidogenic acute regulatory protein gene (STAR). The defective mechanisms here are failures in ACTH ligand binding and/or receptor trafficking for MC2R and MRAP and, in the case of STAR mutations, inefficient cholesterol transport to allow steroidogenesis to proceed. Novel gene defects in FGD have recently been recognised in mini-chromosome maintenance-deficient 4 homologue (MCM4) and nicotinamide nucleotide transhydrogenase (NNT). MCM4 is one part of a DNA repair complex essential for DNA replication and genome stability, whilst NNT is involved in the glutathione redox system that protects cells against reactive oxygen species. The finding of mutations in these two genes implicates new pathogenetic mechanisms at play in FGD, and implies that the adrenal cortex is exquisitely sensitive to replicative and oxidative stresses.
authors: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors: E
authors: E
authors: Meimaridou
authors: C R
authors: CR
authors: Hughes
authors: J
authors: J
authors: Kowalczyk
authors: L F
authors: LF
authors: Chan
authors: A J L
authors: AJ
authors: Clark
authors: L A
authors: LA
authors: Metherell
mesh_terms: D000309:Adrenal Insufficiency / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics; D018043:Receptors, Corticotropin / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D043202:Steroid Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism; D013256:Steroids / Q000096:biosynthesis
chemical_list: C458099:MRAP protein, human; D008565:Membrane Proteins; D044103:Receptor, Melanocortin, Type 2; D018043:Receptors, Corticotropin; D013256:Steroids