Gonadotrophin receptors.
Precocious puberty may be gonadotrophin-dependent, due to premature activation of the hypothalamic GnRH pulse generator, or gonadotrophin-independent wherein serum LH and FSH levels are undetectable despite near-adult levels of gonadal steroidogenesis. In one form of gonadotrophin-independent familial male precocious puberty (FMPP) activating mutations of the LH receptor cause constitutive activation of the cAMP signal transduction cascade in Leydig cells with attendant testosterone biosynthesis. The LH receptor is a member of the seven transmembrane group of receptors coupled to signal transduction through GTP binding intermediate proteins. In FMPP the initial mutations were described in the sixth membrane spanning domain close to the third intracellular loop which is known to be important for coupling to the subunit of the stimulatory GTP binding protein Gs. Subsequently, activating mutations at several other sites in the LH receptor have been described. Activating mutations in the second step of the signalling cascade, the GTP binding protein Gs, have been described in sporadic somatotrophinomas in the pituitary and solitary thyroid adenomas. The McCune-Albright syndrome may also be rarely associated with pituitary and thyroid adenomas, in addition to the more common polyostotic fibrosus dysplasia and gonadotrophin-independent precocious puberty. Thus, in the luteinized ovarian tissue of patients with this condition activating mutations in Gs alpha subunit have been described at codon 201. These mutations are somatic, not germ line, and only one allele needs to be affected as they are dominant. In an uncommon form of male pseudohermaphroditism associated with hypergonadotrophic hypogonadism and Leydig cell hypoplasia, inactivating mutations of the LH receptor are described. These, too, are in the sixth transmembrane domain and both alleles must be mutant as the condition is autosomal recessive. These 'experiments of nature' have provided invaluable insights into the structure-function relations of the LH receptor, and the mutations described have been recreated and studied in vitro, where the predicted activation or failure to stimulate steroidogenesis confirm their pathogenic nature. As yet no such activating or inhibiting mutations in the FSH receptor gene have been described, but it is likely these will be forthcoming in future.
Clayton
R N
RN
School of Postgraduate Medicine, Keele University, Hartshill, Stoke-on-Trent, UK.
D012734:Disorders of Sex Development / Q000235:genetics; D005359:Fibrous Dysplasia, Polyostotic / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D011629:Puberty, Precocious / Q000235:genetics; D011974:Receptors, LH / Q000235:genetics
D011974:Receptors, LH