title: A missense mutation in the second transmembrane segment of the luteinizing hormone receptor causes familial male-limited precocious puberty.
abstract: Patients with familial male-limited precocious puberty present with early onset of puberty. Several missense mutations in the LH receptor gene that cause amino acid substitutions in the sixth transmembrane segment of the receptor protein have been shown to be a cause of the disorder. We have identified a novel LH receptor gene mutation in a patient with familial male-limited precocious puberty that results in a threonine for methionine substitution at position 398 in the second transmembrane segment of the receptor protein. In vitro expression in human embryonic kidney 293 cells of this LH receptor mutant and two previously described LH receptor mutants showed that cAMP production in the absence of hormone was elevated up to 25-fold compared to the basal level of the wild-type receptor. The ED50 values of hormone-induced cAMP production were within the same range for wild-type and mutant receptors, but maximal hormone-induced cAMP production was relatively low for mutant receptors. We also produced receptors containing amino acid substitutions in both the second and sixth transmembrane segments. For these double mutants, basal receptor activities were similar to the basal activities observed in single mutants, whereas hormone-induced receptor activation was almost completely abolished.
authors.affiliation: Department of Endocrinology and Reproduction, Erasmus University Rotterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Kraaij
authors.forename: M
authors.initials: M
authors.lastname: Post
authors.forename: H
authors.initials: H
authors.lastname: Kremer
authors.forename: E
authors.initials: E
authors.lastname: Milgrom
authors.forename: W
authors.initials: W
authors.lastname: Epping
authors.forename: H G
authors.initials: HG
authors.lastname: Brunner
authors.forename: J A
authors.initials: JA
authors.lastname: Grootegoed
authors.forename: A P
authors.initials: AP
authors.lastname: Themmen
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D002675:Child, Preschool; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D008297:Male; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D011629:Puberty, Precocious / Q000235:genetics*; D011974:Receptors, LH / Q000235:genetics* / Q000502:physiology; D012727:Sex Characteristics
chemical_list: D015335:Molecular Probes; D011974:Receptors, LH; D000242:Cyclic AMP