Mutations of the KISS1 Gene Associated with Central Precocious Puberty

Context: Kisspeptin, encoded by the KISS1 gene, is a key stimulatory factor of GnRH secretion and puberty onset. Inactivating mutations of its receptor (KISS1R) cause isolated hypogonadotropic hypogonadism (IHH). A unique KISS1R activating mutation was described in central precocious puberty (CPP). Objective: To investigate KISS1 mutations in patients with idiopathic CPP and normosmic IHH. Patients: Eighty-three children with CPP (77 girls) and 61 patients with IHH (40 men) were studied. The control group consisted of 200 individuals with normal pubertal development. Methods: The promoter region and the 3 exons of KISS1 were amplified and sequenced. Cells expressing KISS1R were stimulated with synthetic human wild-type or mutant kisspeptin-54 (kp54) and inositol phosphate accumulation was measured. In a second set of experiments, kp54 was pre-incubated in human serum prior to stimulation of the cells. Results: Two novel KISS1 missense mutations, p.P74S and p.H90D, were identified in three unrelated children with idiopathic CPP. Both mutations were absent in 400 control alleles. The p.P74S mutation was identified in the heterozygous state in a boy who developed CPP at 1 yr of age. The p.H90D mutation was identified in the homozygous state in two unrelated girls with CPP. In vitro studies revealed that the capacity of the P74S and H90D mutants to stimulate IP production was similar to the wild-type. After pre-incubation of wild-type and mutant kp54’s in human serum, the capacity to stimulate signal transduction was significantly greater for P74S compared to the wild-type, suggesting that the p.P74S variant is more stable. Only polymorphisms were found in the IHH group. Conclusion: Two KISS1 mutations were identified in unrelated patients with idiopathic CPP. The p.P74S variant was associated with higher kisspeptin resistance to degradation in comparison to the wild-type, suggesting a role for this mutation in the precocious puberty phenotype. Infants of Women with Polycystic Ovary Syndrome have Lower Cord Blood Androstenedione and Estradiol Levels Helen Anderson, Naomi Fogel, Stefan K. Grebe, Ravinder J. Singh, Robert L. Taylor, and Andrea Dunaif (J Clin Endocrinol Metab, 10.1210/jc.2009-2651) ABSTRACT Context: Prenatal androgen excess can cause a phenocopy of polycystic ovary syndrome (PCOS) in mammals. Retrospective studies have suggested that girls at risk for PCOS have low birth weight and prospective studies have suggested an increased prevalence of small for gestational age offspring in women with PCOS. Objective: To determine whether infants of women with PCOS have reduced birth weight or increased intrauterine androgen levels. Design: Prospective case-control study. Endocrine Reviews, April 2010, 31(2):254–263 edrv.endojournals.org 255Context: Prenatal androgen excess can cause a phenocopy of polycystic ovary syndrome (PCOS) in mammals. Retrospective studies have suggested that girls at risk for PCOS have low birth weight and prospective studies have suggested an increased prevalence of small for gestational age offspring in women with PCOS. Objective: To determine whether infants of women with PCOS have reduced birth weight or increased intrauterine androgen levels. Design: Prospective case-control study. Endocrine Reviews, April 2010, 31(2):254–263 edrv.endojournals.org 255