Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure

Hypergonadotropic ovarian dysgenesis (ODG) with normal karyotype is a heterogeneous condition that in some cases displays Mendelian recessive inheritance. By systematically searching for linkage in multiplex affected families, we mapped a locus for ODG to chromosome 2p. As the previously cloned foll...

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Bibliographic Details
Published in:Cell 1995-09, Vol.82 (6), p.959-968
Main Authors: Aittomäki, Kristiina, Dieguez Lucena, JoséLuis, Pakarinen, Pirjo, Sistonen, Pertti, Tapanainen, Juha, Gromoll, Jörg, Kaskikari, Riitta, Sankila, Eeva-Marja, Lehväslaiho, Heikki, Reyes Engel, Armando, Nieschlag, Eberhard, Huhtaniemi, Ilpo, de la Chapelle, Albert
Format: Article
Language:English
Subjects:
Base Sequence
Cells, Cultured - physiology
Chromosomes, Human, Pair 2
Electrophoresis
Family Health
Female
Genetic Linkage
Genetic Testing
Haplotypes - genetics
Humans
Incidence
Molecular Sequence Data
Mutation - physiology
Pedigree
Polymorphism, Genetic
Primary Ovarian Insufficiency - epidemiology
Primary Ovarian Insufficiency - etiology
Primary Ovarian Insufficiency - genetics
Receptors, FSH - genetics
Sequence Analysis, DNA
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Summary:Hypergonadotropic ovarian dysgenesis (ODG) with normal karyotype is a heterogeneous condition that in some cases displays Mendelian recessive inheritance. By systematically searching for linkage in multiplex affected families, we mapped a locus for ODG to chromosome 2p. As the previously cloned follicle-stimulating hormone receptor (FSHR) gene had been assigned to 2p, we searched it for mutations. A C566T transition in exon 7 of FSHR predicting an Ala to Val substitution at residue 189 in the extracellular ligand-binding domain segregated perfectly with the disease phenotype. Expression of the gene in transfected cells demonstrated a dramatic reduction of binding capacity and signal transduction, but apparently normal ligand-binding affinity of the mutated receptor. We conclude that the mutation causes ODG in these families.
ISSN:0092-8674
1097-4172
DOI:10.1016/0092-8674(95)90275-9