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 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.
Aittomäki
K
K
Department of Medical Genetics, University of Helsinki, Finland.
Lucena
J L
JL
Pakarinen
P
P
Sistonen
P
P
Tapanainen
J
J
Gromoll
J
J
Kaskikari
R
R
Sankila
E M
EM
Lehväslaiho
H
H
Engel
A R
AR
Nieschlag
E
E
Huhtaniemi
I
I
de la Chapelle
A
A
D001483:Base Sequence; D002478:Cells, Cultured / Q000502:physiology; D002889:Chromosomes, Human, Pair 2; D004586:Electrophoresis; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015994:Incidence; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology*; D010375:Pedigree; D011110:Polymorphism, Genetic; D016649:Primary Ovarian Insufficiency / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D011962:Receptors, FSH / Q000235:genetics*; D017422:Sequence Analysis, DNA
D011962:Receptors, FSH