A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty

• Published in: Nature (London) 1993-10, Vol.365 (6447), p.652-654
• Main Authors: Shenker, Andrew, Laue, Louisa, Kosugi, Shinji, Merendino, John J, Minegishi, Takashi, Cutler, Gordon B
• Format: Article
• Language: English
• Subjects: Adenine; Amino Acid Sequence; Animals; Base Sequence; Biochemistry; Biological and medical sciences; Cell Line; Chorionic Gonadotropin - pharmacology; Cyclic AMP - metabolism; Deoxyribonuclease HpaII; Deoxyribonucleases, Type II Site-Specific; DNA Mutational Analysis; DNA Primers; Endocrinopathies; Female; Guanine; Hormones; Humanities and Social Sciences; Humans; Hypothalamus. Hypophysis. Epiphysis (diseases); letter; Leydig Cells - metabolism; luteinizing hormone; Male; man; Medical sciences; Men; Molecular Sequence Data; multidisciplinary; Mutation; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Pedigree; Polymerase Chain Reaction; puberty; Puberty, Precocious - genetics; Puberty, Precocious - metabolism; receptors; Receptors, LH - genetics; Receptors, LH - metabolism; Recombinant Proteins - genetics; Science; Transfection
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/365652a0

FAMILIAL male precocious puberty (FMPP) is a gonadotropin-independent disorder that is inherited in an autosomal dominant, male-limited pattern 1–5 . Affected males generally exhibit signs of puberty by age 4. Testosterone production and Ley dig cell hyper-plasia occur in the context of prepubertal levels of luteinizing hormone (LH) 3–5 . The LH receptor is a member of the family of G-protein-coupled receptors 6,7 , and we hypothesized that FMPP might be due to a mutant receptor that is activated in the presence of little or no agonist 8–12 . A single A → G base change that results in substitution of glycine for aspartate at position 578 in the sixth transmembrane helix of the LH receptor was found in affected individuals from eight different families. Linkage of the mutation to FMPP was supported by restriction-digest analysis. COS-7 cells expressing the mutant LH receptor exhibited markedly increased cyclic AMP production in the absence of agonist, suggesting that autonomous Leydig cell activity in FMPP is caused by a constitutively activated LH receptor.