Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 364, Issue 1-2, Pages 71-82Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2012.08.011
Keywords
Follicle-stimulating hormone; Follicle-stimulating hormone receptor; Constitutive activation; Mutation; Internalization; Desensitization
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Funding
- CONACyT (Mexico) [78824, 86881]
- FIS-Instituto Mexicano del Seguro Social, Mexico [R-2007-3606-17]
- National Institutes of Health (Bethesda, MD) [HD18407]
- Region Centre, Institut National de la Recherche Agronomique and Agence Nationale de la Recherche
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Activating mutations in the follicle-stimulating hormone (FSH) receptor (FSHR) gene are rarely detected due to the absence of a clearly defined phenotype, particularly in men. We here report the biochemical features of a novel mutation in the first extracellular loop of the FSHR. The mutation (N431I) was detected in an asymptomatic man exhibiting normal spermatogenesis, suppressed serum FSH, and normal or elevated levels of biochemical markers of FSH action. Employing different experimental strategies on HEK-293 cells transiently expressing the N431I FSHR mutant, we found that the mutation led to decreased cell surface plasma membrane expression of the receptor protein, but conferred a low level of constitutive activity associated with markedly altered agonist-stimulated desensitization and internalization. These latter features may contribute and/or amplify the persistent activation of the receptor in both absence and presence of agonist and provide new insights into opportunities for adjuvant therapies based on disruption of these processes. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
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