Mutations of the KISS1 Gene in Disorders of Puberty

SILVEIRA LG; NOEL SD; SILVEIRA-NETO AP; ABREU AP; BRITO VN; SANTOS MG; BIANCO SDC; KUOHUNG W; XU S; GRYNGARTEN M; ESCOBAR ME; ARNHOLD IJ; MENDONCA BB; HAISER UB; LATRONICO AC

JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM

ENDOCRINE SOC

Lugar: Springfield, Ill.; Año: 2010 vol. 95 p. 2276 - 2280

0021-972X

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). (IHH). A unique KISS1R-activating mutation was described in central precocious puberty (CPP). 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). (IHH). A unique KISS1R-activating mutation was described in central precocious puberty (CPP). 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). (IHH). A unique KISS1R-activating mutation was described in central precocious puberty (CPP). KISS1R) cause isolated hypogonadotropic hypogonadism (IHH). A unique KISS1R-activating mutation was described in central precocious puberty (CPP).KISS1R-activating mutation was described in central precocious puberty (CPP). Objective: Our objective was to investigate KISS1 mutations in patients with idiopathic CPP and normosmic IHH. normosmic IHH. Our objective was 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. The control group consisted of 200 individuals with normal pubertal development. 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 three exons of KISS1 were amplified and sequenced. Cells expressing KISS1R were stimulated with synthetichumanwild-type or mutant kisspeptin-54 (kp54), and inositol phosphate accumulation was measured. In a second set of experiments, kp54 was preincubated in human serum before stimulation of the cells. and inositol phosphate accumulation was measured. In a second set of experiments, kp54 was preincubated in human serum before stimulation of the cells. expressing KISS1R were stimulated with synthetichumanwild-type or mutant kisspeptin-54 (kp54), and inositol phosphate accumulation was measured. In a second set of experiments, kp54 was preincubated in human serum before stimulation of the cells. and inositol phosphate accumulation was measured. In a second set of experiments, kp54 was preincubated in human serum before stimulation of the cells. The promoter region and the three exons of KISS1 were amplified and sequenced. Cells expressing KISS1R were stimulated with synthetichumanwild-type or mutant kisspeptin-54 (kp54), and inositol phosphate accumulation was measured. In a second set of experiments, kp54 was preincubated in human serum before stimulation of the cells. and inositol phosphate accumulation was measured. In a second set of experiments, kp54 was preincubated in human serum before stimulation of the cells. KISS1R were stimulated with synthetichumanwild-type or mutant kisspeptin-54 (kp54), and inositol phosphate accumulation was measured. In a second set of experiments, kp54 was preincubated in human serum before 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 preincubation of wild-typeandmutantkp54inhumanserum,thecapacity to stimulate signal transductionwassignificantly greater for P74Scomparedwith the wild type, suggesting that the p.P74S variant is more stable. Only polymorphisms were found in the IHH group. revealed that the capacity of the P74S and H90D mutants to stimulate IP production was similar to the wild type. After preincubation of wild-typeandmutantkp54inhumanserum,thecapacity to stimulate signal transductionwassignificantly greater for P74Scomparedwith the wild type, suggesting that the p.P74S variant is more stable. Only polymorphisms were found in the IHH group. 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 preincubation of wild-typeandmutantkp54inhumanserum,thecapacity to stimulate signal transductionwassignificantly greater for P74Scomparedwith the wild type, suggesting that the p.P74S variant is more stable. Only polymorphisms were found in the IHH group. revealed that the capacity of the P74S and H90D mutants to stimulate IP production was similar to the wild type. After preincubation of wild-typeandmutantkp54inhumanserum,thecapacity to stimulate signal transductionwassignificantly greater for P74Scomparedwith the wild type, suggesting that the p.P74S variant is more stable. Only polymorphisms were found in the IHH group. 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 preincubation of wild-typeandmutantkp54inhumanserum,thecapacity to stimulate signal transductionwassignificantly greater for P74Scomparedwith the wild type, suggesting that the p.P74S variant is more stable. Only polymorphisms were found in the IHH group. revealed that the capacity of the P74S and H90D mutants to stimulate IP production was similar to the wild type. After preincubation of wild-typeandmutantkp54inhumanserum,thecapacity to stimulate signal transductionwassignificantly greater for P74Scomparedwith the wild type, suggesting that the p.P74S variant is more stable. Only polymorphisms were found in the IHH group. In vitro studies revealed that the capacity of the P74S and H90D mutants to stimulate IP production was similar to the wild type. After preincubation of wild-typeandmutantkp54inhumanserum,thecapacity to stimulate signal transductionwassignificantly greater for P74Scomparedwith the wild type, suggesting that the p.P74S variant is more stable. Only polymorphisms were found in the IHH group. Conclusion:TwoKISS1mutationswereidentified in unrelated patientswithidiopathic CPP.Thep.P74S variant was associated with higher kisspeptin resistance to degradation in comparison with the wild type, suggestingarole for this mutation in the precocious puberty phenotype variant was associated with higher kisspeptin resistance to degradation in comparison with the wild type, suggestingarole for this mutation in the precocious puberty phenotype TwoKISS1mutationswereidentified in unrelated patientswithidiopathic CPP.Thep.P74S variant was associated with higher kisspeptin resistance to degradation in comparison with the wild type, suggestingarole for this mutation in the precocious puberty phenotype