Unidade de Endocrinologia do Desenvolvimento, Hospital das Clinicas, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, SP 05403-900, Brasil.
J Clin Endocrinol Metab. 2010 May;95(5):2276-80. doi: 10.1210/jc.2009-2421. Epub 2010 Mar 17.
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).
Our objective was to investigate KISS1 mutations in patients with idiopathic CPP and normosmic IHH.
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 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.
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.
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.
Kisspeptin 由 KISS1 基因编码，是 GnRH 分泌和青春期启动的关键刺激因素。其受体（KISS1R）的失活突变可导致孤立性促性腺激素缺乏性性腺功能减退症（IHH）。一种独特的 KISS1R 激活突变已在中枢性性早熟（CPP）中被描述。
我们旨在研究特发性 CPP 和正常嗅觉 IHH 患者的 KISS1 突变。
研究了 83 例 CPP 患儿（77 例女孩）和 61 例 IHH 患者（40 例男性）。对照组由 200 名具有正常青春期发育的个体组成。
扩增并测序了 KISS1 的启动子区域和三个外显子。用合成的人野生型或突变型 kisspeptin-54（kp54）刺激表达 KISS1R 的细胞，并测量肌醇磷酸的积累。在第二组实验中，在刺激细胞之前，将 kp54 在人血清中预孵育。
在 3 名特发性 CPP 无亲缘关系的儿童中发现了两种新的 KISS1 错义突变，p.P74S 和 p.H90D。这两种突变均不存在于 400 个对照等位基因中。p.P74S 突变在 1 岁时发生 CPP 的男孩中为杂合状态。p.H90D 突变在 2 名有 CPP 的无亲缘关系的女孩中为纯合状态。体外研究表明，P74S 和 H90D 突变体刺激 IP 产生的能力与野生型相似。在 kp54 野生型和突变型在人血清中预孵育后，与野生型相比，P74S 刺激信号转导的能力显著增强，表明 p.P74S 变体更稳定。在 IHH 组中仅发现了多态性。
在无亲缘关系的特发性 CPP 患者中发现了两种 KISS1 突变。与野生型相比，p.P74S 变体对降解的 kisspeptin 抵抗性更高，提示该突变在性早熟表型中起作用。
