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While evaluating a Saudi family with several first cousin marriages in which many offspring had "idiopathic hypogonadotropic hypogonadism" transmitted as an autosomal recessive trait, the authors identified a locus on chromosome 19p13.3.1,2 This locus had a homozygous mutation of GPR54 (chromosome 19p13.3, OMIM 604161, encoding an orphan G-protein receptor termed GPR54) at codon 148 in which serine was substituted for leucine (Leu148Ser). An unrelated patient was demonstrated to be a compound heterozygote with mutations in both alleles of GPR54 - Arg331Stop leading to a truncated product and Stop399Arg - the latter resulting in an elongated protein product. In vitro , all mutations were found to decrease signal transduction through phospholipase C in response to the natural ligand of this receptor - kisspeptin-1 - sequence 112-121 (encoded by KISS1 , chromosome 1q32, OMIM 603286). Kisspeptin-1 [sequence 68-121] suppresses metastases of melanoma and breast carcinoma experimentally. This 54 amino acid peptide, termed metastatin, is secreted by the placenta. In the compound heterozygotic subject, there were low basal concentrations of LH and testosterone that increased during pulsatile administration of exogenous GnRH; interestingly, this patient was more sensitive to the gonadotropin stimulating effects of GnRH than were comparable patients with hypogonadotropic hypogonadism without this specific genetic mutation.
The investigators extended these studies by developing a "knock-out" mouse model of GPR54-/- that reproduced the clinical picture. The GPR54+/- heterozygous mice had normal growth and fertility. The GPR54-/- deficient animals of both genders were hypogonadotropic with small gonads, hypotrophic internal genitalia, and absence of secondary sexual characteristics. Interestingly, the adrenal glands of the GPR54-/- animals were immature as well. Serum gonadotropin and sex hormone levels were low in GPR54-/- animals, but LH and FSH values increased following administration of exogenous GnRH, but the hypothalamic concentrations of GnRH were normal. The authors conclude that the kisspeptin-GPR54 system is important in the regulation of GnRH processing or secretion in the hypothalamus rather than in the movement of GnRH secreting neurons from their embryologic site of origin in the olfactory placode (the error in Kallmann syndrome) or in the synthesis of GnRH itself.
Seminara SB, et al. The GPR54 gene as a regulator of puberty. N Engl J Med 2003;349:1614-1627.
Editor's Comment: This exciting report exemplifies the best of clinical investigation employing the most up-to-date technology in a multi-institutional collaborative that should serve as a model for future studies. The identification of a G-protein receptor (and its aptly named endogenous ligand - kisspeptin) that are involved in the regulation of GnRH release opens an entirely new control system of the reproductive endocrine axis,3 a finding analogous in importance to the discovery of the role of ghrelin in the regulation of growth hormone secretion4 and energy metabolism. Elucidation of the mechanism(s) by which this unit regulates GnRH secretion is eagerly anticipated. One can envision many future studies of the kisspeptin-GPR54 axis. Perhaps it is involved in the development of normal puberty. Might polymorphisms of its component genes or signal transduction system account for variations in the early or delayed onset of adolescence? Are gain-of-function mutations in GPR54 present in some children with idiopathic central precocious puberty? Does the development of gonadotropin secreting tumors involve this pathway? Since metastatin is secreted by the placenta, this suggests that it has a physiologic role during gestation - possibly in regulation of fetal gonadotropin secretion. Future studies are eagerly and impatiently awaited.
Allen Root, MD
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