title: Normal testicular function without detectable follicle-stimulating hormone. A novel mutation in the follicle-stimulating hormone receptor gene leading to apparent constitutive activity and impaired agonist-induced desensitization and internalization.
abstract: 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.
authors.affiliation: Research Unit in Reproductive Medicine, Hospital de Ginecobstetricia Luis Castelazo Ayala, Instituto Mexicano del Seguro Social, Mexico 01090, DF, Mexico. pcglez081@yahoo.com.mx
authors.forename: Patricia
authors.initials: P
authors.lastname: Casas-González
authors.forename: Hugo E
authors.initials: HE
authors.lastname: Scaglia
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pérez-Solís
authors.forename: Guillaume
authors.initials: G
authors.lastname: Durand
authors.forename: Javier
authors.initials: J
authors.lastname: Scaglia
authors.forename: Teresa
authors.initials: T
authors.lastname: Zariñán
authors.forename: James A
authors.initials: JA
authors.lastname: Dias
authors.forename: Eric
authors.initials: E
authors.lastname: Reiter
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ulloa-Aguirre
mesh_terms: D019390:Arrestins / Q000494:pharmacology*; D001483:Base Sequence; D000242:Cyclic AMP / Q000378:metabolism; D005640:Follicle Stimulating Hormone / Q000378:metabolism / Q000494:pharmacology; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D008156:Luciferases; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011962:Receptors, FSH / Q000235:genetics* / Q000378:metabolism; D013091:Spermatogenesis / Q000187:drug effects* / Q000235:genetics; D013737:Testis / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D055815:Young Adult
chemical_list: D019390:Arrestins; D011962:Receptors, FSH; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP; D008156:Luciferases