PMID- 10551778
OWN - NLM
STAT- MEDLINE
DCOM- 19991130
LR  - 20161124
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 13
IP  - 11
DP  - 1999 Nov
TI  - New natural inactivating mutations of the follicle-stimulating hormone receptor: 
      correlations between receptor function and phenotype.
PG  - 1844-54
AB  - 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.
FAU - Touraine, P
AU  - Touraine P
AD  - Department of Endocrinology and Reproductive Medicine, Hopital Necker, Institut
      Federatif de Recherche (IFR-NEM), Paris, France.
FAU - Beau, I
AU  - Beau I
FAU - Gougeon, A
AU  - Gougeon A
FAU - Meduri, G
AU  - Meduri G
FAU - Desroches, A
AU  - Desroches A
FAU - Pichard, C
AU  - Pichard C
FAU - Detoeuf, M
AU  - Detoeuf M
FAU - Paniel, B
AU  - Paniel B
FAU - Prieur, M
AU  - Prieur M
FAU - Zorn, J R
AU  - Zorn JR
FAU - Milgrom, E
AU  - Milgrom E
FAU - Kuttenn, F
AU  - Kuttenn F
FAU - Misrahi, M
AU  - Misrahi M
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Receptors, FSH)
RN  - 0 (Recombinant Proteins)
RN  - 9002-68-0 (Follicle Stimulating Hormone)
RN  - EC 4.6.1.1 (Adenylyl Cyclases)
SB  - IM
MH  - Adenylyl Cyclases/drug effects/metabolism
MH  - Adult
MH  - Amenorrhea/drug therapy/*genetics
MH  - Animals
MH  - COS Cells/drug effects/metabolism
MH  - Female
MH  - Follicle Stimulating Hormone/pharmacology/therapeutic use
MH  - Gene Silencing
MH  - Humans
MH  - Immunohistochemistry
MH  - Male
MH  - *Mutation
MH  - Ovary/diagnostic imaging/pathology/*physiopathology
MH  - Phenotype
MH  - Primary Ovarian Insufficiency/drug therapy/genetics
MH  - Protein Processing, Post-Translational
MH  - Receptors, FSH/drug effects/*genetics/metabolism
MH  - Recombinant Proteins/genetics/metabolism
MH  - Sequence Analysis
MH  - Ultrasonography
EDAT- 1999/11/07 00:00
MHDA- 1999/11/07 00:01
CRDT- 1999/11/07 00:00
PHST- 1999/11/07 00:00 [pubmed]
PHST- 1999/11/07 00:01 [medline]
PHST- 1999/11/07 00:00 [entrez]
AID - 10.1210/mend.13.11.0370 [doi]
PST - ppublish
SO  - Mol Endocrinol. 1999 Nov;13(11):1844-54. doi: 10.1210/mend.13.11.0370.