A CONSTITUTIVELY ACTIVATING MUTATION OF THE LUTEINIZING-HORMONE RECEPTOR IN FAMILIAL MALE PRECOCIOUS PUBERTY

FAMILIAL male precocious puberty (FMP) is a gonadotropin-independent d isorder that is inherited in an autosomal dominant, male-limited patte rn1-5. Affected males generally exhibit signs of puberty by age 4. Tes tosterone production and Leydig cell hyperplasia 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 receptors6,7, and we hy pothesized that FMPP might be due to a mutant receptor that is activat ed in the presence of little or no agonist8-12 . A single A --> G base change that results in substitution of glycine for aspartate at posit ion 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 c ells expressing the mutant LH receptor exhibited markedly increased cy clic AMP production in the absence of agonist, suggesting that autonom ous Leydig cell activity in FMPP is caused by a constitutively activat ed LH receptor.