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.