A MUTATION IN THE FIRST TRANSMEMBRANE DOMAIN OF THE LUTROPIN RECEPTORCAUSES MALE PRECOCIOUS PUBERTY

We describe a patient with onset of puberty at the age of 5 yr, charac terized by accelerated growth, enlargement of genitalia, pubarche, and serum hormone levels compatible with noncentral precocious puberty. E xon 11 of the LH receptor gene was amplified from genomic DNA by PCR a nd directly sequenced. We identified a heterozygous C to T base change at nucleotide position 1126, exchanging codon 373 from Ala to Val in the first transmembrane domain. The LH receptor sequence of the parent s was normal. The mutated receptor displayed an up to 7.5-fold increas e in basal cAMP production compared to that of the wild-type receptor in transiently transfected COS-7 cells. Treatment of the patient with ketoconazole resulted in inconsistent suppression of serum testosteron e levels. At the age of 9.1 yr, central activation of the hypothalamic -pituitary-gonadal axis occurred. Additional treatment with a GnRH ago nist led to complete suppression of testosterone secretion. This is th e first description of constitutive activation of the LH receptor in t he first transmembrane segment. It suggests the involvement of the fir st transmembrane helix in signal transduction and provides further ins ight into the structural organization of the seven transmembrane domai ns of the glycoprotein hormone receptor proteins.