title: A novel mutation of the luteinizing hormone receptor gene causing male gonadotropin-independent precocious puberty.
abstract: Familial male-limited precocious puberty (FMPP) is an autosomal dominant gonadotropin-independent disorder. Affected males generally develop signs of precocious puberty in early childhood. They typically show Leydig cell hyperplasia and increased testosterone production typical for their age, whereas circulating LH concentrations remain prepubertal. Several dominant point mutations of the LH receptor gene were identified in pedigrees with familial male-limited precocious puberty and were shown to cosegregate with the disease. Here we report a novel heterozygote point mutation in the LH receptor gene of a Brazilian boy with gonadotropin-independent precocious puberty. This mutation substitutes alanine 568 with valine at the carboxyterminus of the third cytosolic loop of the LH receptor. The unoccupied mutant receptors confer constitutive activation of adenyl cyclase activity when expressed in COS-7 cells, resulting in 4-fold higher cAMP concentrations over baseline compared with cells expressing an equivalent number of wild-type receptors. The affinity of the mutant receptors to 125I-labeled human LH was not altered compared with the wild type. Mutations of the homologue alanine residue in the alpha 1-adrenergic (in vitro), FSH (in vitro), and TSH (naturally occurring) receptors also result in constitutive adenyl cyclase activation, suggesting that this alanine residue is crucial for signal transduction and a potential site for upregulatory/oncogenic mutations in G-protein coupled receptors.
authors.affiliation: Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, Maryland 20892, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Latronico
authors.forename: J
authors.initials: J
authors.lastname: Anasti
authors.forename: I J
authors.initials: IJ
authors.lastname: Arnhold
authors.forename: B B
authors.initials: BB
authors.lastname: Mendonça
authors.forename: S
authors.initials: S
authors.lastname: Domenice
authors.forename: M C
authors.initials: MC
authors.lastname: Albano
authors.forename: K
authors.initials: K
authors.lastname: Zachman
authors.forename: B L
authors.initials: BL
authors.lastname: Wajchenberg
authors.forename: C
authors.initials: C
authors.lastname: Tsigos
mesh_terms: D000409:Alanine; D000595:Amino Acid Sequence; D000728:Androgens / Q000097:blood; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000235:genetics; D017931:DNA Primers; D005640:Follicle Stimulating Hormone / Q000097:blood* / Q000378:metabolism; D006580:Genetic Carrier Screening; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D011629:Puberty, Precocious / Q000097:blood / Q000235:genetics*; D011974:Receptors, LH / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D012016:Reference Values; D014162:Transfection; D014633:Valine
chemical_list: D000728:Androgens; D017931:DNA Primers; D011974:Receptors, LH; D011994:Recombinant Proteins; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D004247:DNA; D000242:Cyclic AMP; D014633:Valine; D000409:Alanine