title: New natural inactivating mutations of the follicle-stimulating hormone receptor: correlations between receptor function and phenotype.
abstract: Premature ovarian failure occurs in almost 1% of women under age 40. Molecular alterations of the FSH receptor (FSHR) have recently been described. A first homozygous mutation of the FSHR was identified in Finland. More recently, we described two new mutations of the FSHR in a woman presenting a partial FSH-resistance syndrome (patient 1). We now report new molecular alterations of the FSHR in another woman (patient 2) who presented at the age of 19 with primary amenorrhea contrasting with normal pubertal development. She had high plasma FSH, and numerous ovarian follicles up to 3 mm in size were evidenced by ultrasonography. Histological and immunohistochemical examination of ovarian biopsies revealed the presence of a normal follicular development up to the antral stage and disruption at further stages. DNA sequencing showed two heterozygous mutations: Asp224Val in the extracellular domain and Leu601Val in the third extracellular loop of FSHR. Cells transfected with expression vectors encoding the wild type or the mutated Leu601Val receptors bound hormone with similar affinity, whereas binding was barely detectable with the Asp224Val mutant. Confocal microscopy showed the latter to have an impaired targeting to the cell membrane. This was confirmed by its accumulation as a mannose-rich precursor. Adenylate cyclase stimulation by FSH of the Leu601Val mutant receptor showed a 12+/-3% residual activity, whereas in patient 1 a 24+/-4% residual activity was detected for the Arg573Cys mutant receptor. These results are in keeping with the fact that estradiol and inhibin B levels were higher in patient 1 and that stimulation with recombinant FSH did not increase follicular size, estradiol, or inhibin B levels in patient 2 in contrast to what was observed for patient 1. Thus, differences in the residual activity of mutated FSHR led to differences in the clinical, biological, and histological phenotypes of the patient.
authors.affiliation: Department of Endocrinology and Reproductive Medicine, Hôpital Necker, Institut Fédératif de Recherche (IFR-NEM), Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Touraine
authors.forename: I
authors.initials: I
authors.lastname: Beau
authors.forename: A
authors.initials: A
authors.lastname: Gougeon
authors.forename: G
authors.initials: G
authors.lastname: Meduri
authors.forename: A
authors.initials: A
authors.lastname: Desroches
authors.forename: C
authors.initials: C
authors.lastname: Pichard
authors.forename: M
authors.initials: M
authors.lastname: Detoeuf
authors.forename: B
authors.initials: B
authors.lastname: Paniel
authors.forename: M
authors.initials: M
authors.lastname: Prieur
authors.forename: J R
authors.initials: JR
authors.lastname: Zorn
authors.forename: E
authors.initials: E
authors.lastname: Milgrom
authors.forename: F
authors.initials: F
authors.lastname: Kuttenn
authors.forename: M
authors.initials: M
authors.lastname: Misrahi
mesh_terms: D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000568:Amenorrhea / Q000188:drug therapy / Q000235:genetics*; D000818:Animals; D019556:COS Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology / Q000627:therapeutic use; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D010053:Ovary / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D010641:Phenotype; D016649:Primary Ovarian Insufficiency / Q000188:drug therapy / Q000235:genetics; D011499:Protein Processing, Post-Translational; D011962:Receptors, FSH / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017421:Sequence Analysis; D014463:Ultrasonography
chemical_list: D011962:Receptors, FSH; D011994:Recombinant Proteins; D005640:Follicle Stimulating Hormone; D000262:Adenylyl Cyclases