Mutations of the KISS1 Gene in Disorders of Puberty

Autor(es):Mostrar menos -

Silveira, L. G. ^[1] ; Noel, S. D. ^[2] ; Silveira-Neto, A. P. ^[3] ; Abreu, A. P. ^[3] ; Brito, V. N. ^[3] ; Santos, M. G. ^[3] ; Bianco, S. D. C. ^[2] ; Kuohung, W. ^[2] ; Xu, S. ^[2] ; Gryngarten, M. ^[4] ; Escobar, M. E. ^[4] ; Arnhold, I. J. P. ^[3] ; Mendonca, B. B. ^[3] ; Kaiser, U. B. ^[2] ; Latronico, A. C. ^[3]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med, Hosp Clin, Lab Hormonios & Genet Mol LIM42, Disciplina Endocrinol & Metabol, Unidade Endocrino, BR-05403900 Sao Paulo - Brazil

^[2] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 - USA

^[3] Harvard Univ, Sch Med, Boston, MA 02115 - USA

^[4] Hosp Ninos Dr Ricardo Gutierrez, Div Endocrinol, Ctr Invest Endocrinol, RA-1425 Buenos Aires, DF - Argentina

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 95, n. 5, p. 2276-2280, MAY 2010.
• Citações Web of Science: 128

Resumo

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: 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. Methods: The promoter region and the three 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 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-type and mutant kp54 in human serum, the capacity to stimulate signal transduction was significantly greater for P74S compared with 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 with the wild type, suggesting a role for this mutation in the precocious puberty phenotype. (J Clin Endocrinol Metab 95: 2276-2280, 2010) (AU)

• Processo FAPESP: 05/55745-4 - Análise do gene KISS1 na puberdade normal e nos distúrbios puberais em humanos
• Beneficiário: Letícia Ferreira Gontijo Silveira
• Modalidade de apoio: Bolsas no Brasil - Doutorado