Abstract | CONTEXT: HYPOTHESIS: The p.R8C ACTH mutant is immunoreactive, but the mutant peptides, ACTH-R8C and α-MSH-R8C, are bioinactive. METHODS: RESULTS: ACTH-R8C was immunoreactive but failed to bind and activate cAMP production in melanocortin-2 receptor (MC2R)-expressing cells, and α-MSH-R8C failed to bind and stimulate cAMP production in MC1R- and MC4R-expressing cells. CONCLUSION: These are the first documented cases of glucocorticoid deficiency due to the secretion of an ACTH molecule that lacks biological bioactivity but conserves immunoreactivity. POMC mutations should thus be considered in patients presenting with apparent ACTH resistance. Our findings also highlight a limitation to immunoassay-based diagnostics and demonstrate the value of genetic analysis. Establishing the molecular etiology of the disorder in our patients allowed cessation of the unnecessary mineralocorticoids. Finally, discovery of this mutation indicates that in humans, the amino acid sequence His(6)Phe(7)Arg(8)Trp(9) is important not only for cAMP activation but also for ACTH binding to MC2R.
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Authors | Mark E Samuels, Nicole Gallo-Payet, Sandra Pinard, Caroline Hasselmann, Fabien Magne, Lysanne Patry, Lucie Chouinard, Jeremy Schwartzentruber, Patricia René, Nicole Sawyer, Michel Bouvier, Anissa Djemli, Edgard Delvin, Céline Huot, Dardye Eugene, Cheri L Deal, Guy Van Vliet, Jacek Majewski, Johnny Deladoëy, FORGE Canada Consortium |
Journal | The Journal of clinical endocrinology and metabolism
(J Clin Endocrinol Metab)
Vol. 98
Issue 2
Pg. 736-42
(Feb 2013)
ISSN: 1945-7197 [Electronic] United States |
PMID | 23293326
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Glucocorticoids
- Receptor, Melanocortin, Type 2
- alpha-MSH
- Adrenocorticotropic Hormone
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Topics |
- Addison Disease
(genetics)
- Adrenocorticotropic Hormone
(genetics)
- Child, Preschool
- Female
- Glucocorticoids
(deficiency)
- Heterozygote
- Homozygote
- Humans
- Hypoglycemia
(genetics)
- Infant
- Male
- Mutation
- Receptor, Melanocortin, Type 2
(genetics)
- alpha-MSH
(genetics)
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