title: A Novel mutation in the FSH receptor inhibiting signal transduction and causing primary ovarian failure.
abstract: Inactivating mutations of the FSH receptor (FSHR) are known to cause ovarian failure with amenorrhea and infertility in women. The first mutation identified in the FSHR gene was a missense mutation (566C-->T, predicting Ala189Val transition) found in several Finnish patients with primary amenorrhea due to ovarian failure. Only five additional, partially or totally inactivating, mutations of the FSHR have been reported. Here, we report a novel FSHR mutation, 1255G-->A, in a Finnish female with primary amenorrhea. The patient was a compound heterozygote for two mutations in the FSHR gene: 566C-->T, the Finnish founder mutation, and 1255G-->A, a previously unidentified mutation. The new mutation is located in exon 10 in the second transmembrane stretch of the FSHR, and it predicts an Ala419Thr change in the protein structure. In functional testing, the mutation was shown to have minimal effect on ligand binding capacity and affinity, but it almost totally abolished the cAMP second messenger response. Neither of the two FSHR mutations (566C-->T or1255G-->A) was identified in 40 other Finnish patients with premature ovarian failure. Based on this and previous studies, FSHR mutations remain a rare cause of ovarian failure.
authors.affiliation: The Murdoch Institute, Melbourne, VIC 3052 Australia.
authors.forename: Elaine
authors.initials: E
authors.lastname: Doherty
authors.forename: Pirjo
authors.initials: P
authors.lastname: Pakarinen
authors.forename: Aila
authors.initials: A
authors.lastname: Tiitinen
authors.forename: Anna
authors.initials: A
authors.lastname: Kiilavuori
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
authors.forename: Susan
authors.initials: S
authors.lastname: Forrest
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence / Q000235:genetics; D019943:Amino Acid Substitution; D001483:Base Sequence / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D009154:Mutation / Q000502:physiology*; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011962:Receptors, FSH / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D011962:Receptors, FSH