A MISSENSE MUTATION IN THE 2ND TRANSMEMBRANE SEGMENT OF THE LUTEINIZING-HORMONE RECEPTOR CAUSES FAMILIAL MALE-LIMITED PRECOCIOUS PUBERTY

Patients with familial male-limited precocious puberty present with ea rly onset of puberty. Several missense mutations in the LH receptor ge ne that cause amino acid substitutions in the sixth transmembrane segm ent of the receptor protein have been shown to be a cause of the disor der. We have identified a novel LH receptor gene mutation in a patient with familial male-limited precocious puberty that results in a threo nine for methionine substitution at position 398 in the second transme mbrane segment of the receptor protein. In vitro expression in human e mbryonic kidney 293 cells of this LH receptor mutant and two previousl y described LH receptor mutants showed that cAMP production in the abs ence of hormone was elevated up to 25-fold compared to the basal level of the wild-type receptor. The ED(50) values of hormone-induced cAMP production were within the same range for Wild-type and mutant recepto rs, but maximal hormone-induced cAMP production was relatively low for mutant receptors. We also produced receptors containing amino acid su bstitutions in both the second and sixth transmembrane segments. For t hese double mutants, basal receptor activities were similar to the bas al activities observed in single mutants, whereas hormone-induced rece ptor activation was almost completely abolished.