title: A case of male-limited precocious puberty caused by a point mutation in the second transmembrane domain of the luteinizing hormone choriogonadotropin receptor gene.
abstract: We describe a Japanese patient with male-limited precocious puberty who has a heterozygous thymine to cytosine (T to C) transition at nucleotide 1193; the mutation encodes a methionine to threonine substitution in residue 398 (M398T) of transmembrane helix 2 of the luteinizing hormone/choriogonadotropin receptor. Transfected into COS-7 cells, M398T exhibited constitutively high basal cAMP levels but retained an agonist-induced cAMP response. The constitutively higher cAMP levels caused by M398T are consistent with Leydig cell activation and precocious puberty in the patient. By comparison to wild type receptor, M398T transfectants have significantly lower agonist-induced inositol phosphate (IP) levels at > 10(-10) M hCG concentrations and a higher apparent affinity for binding hCG. These data suggest that the M398T substitution alters Gq coupling and phospholipase-C activation, as well as Gs, coupling and adenylyl cyclase activity, and changes the conformation of the extracellular domain of the receptor.
authors.affiliation: National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: K
authors.initials: K
authors.lastname: Yano
authors.forename: L D
authors.initials: LD
authors.lastname: Kohn
authors.forename: M
authors.initials: M
authors.lastname: Saji
authors.forename: N
authors.initials: N
authors.lastname: Kataoka
authors.forename: A
authors.initials: A
authors.lastname: Okuno
authors.forename: G B
authors.initials: GB
authors.lastname: Cutler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D003596:Cytosine; D017931:DNA Primers; D005260:Female; D006580:Genetic Carrier Screening; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007564:Japan; D008297:Male; D008961:Models, Structural; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017433:Protein Structure, Secondary; D011629:Puberty, Precocious / Q000235:genetics*; D011974:Receptors, LH / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012727:Sex Characteristics; D013941:Thymine; D014162:Transfection
chemical_list: D006063:Chorionic Gonadotropin; D017931:DNA Primers; D007295:Inositol Phosphates; D011974:Receptors, LH; D011994:Recombinant Proteins; D003596:Cytosine; D013941:Thymine