Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency:: Molecular genetics and clinical spectrum
Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency:: Molecular genetics and clinical spectrum
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DOI：
10.1210/jc.2007-2654
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发表时间：
2008-09-01
影响因子：
5.8
通讯作者：
Pitteloud, Nelly
中科院分区：
文献类型：
--
作者：
Cole, Lindsay W.;Sidis, Yisrael;Pitteloud, Nelly
背景：缺乏前动力蛋白 2 (PROK2) 和前动力蛋白受体 2 (PROKR2) 的小鼠表现出不同程度的嗅球发育不全和 GnRH 神经元迁移缺陷，让人想起人类 GnRH 缺乏症。 目的：我们的目的是筛选一大群患有卡尔曼综合征 (KS) 和正常渗透性特发性肾病的患者 对 PROK2/PROKR2 突变进行低促性腺激素性性腺功能减退 (IHH) 评估，评估其患病率，定义基因型/表型关系，并在体外评估这些突变等位基因的功能。 设计：对 170 名 KS 患者和 154 名 IHH 患者进行 PROK2 和 PROKR2 基因测序。使用 HEK 293 细胞中的早期生长反应 1-荧光素酶测定和中国仓鼠卵巢细胞中的水母发光蛋白测定来检查突变。结果：在 5 位先证者中鉴定出 4 个杂合子和 1 个纯合 PROK2 突变（p. A24P、p. C34Y、p. I50M、p. R73C 和 p. I55fsX1）。 4 名先证者患有 KS，1 名先证者患有 nIHH，并且所有人都没有青春期。除 I50M 外，每种突变肽都会在体外损害受体信号传导。有11名患者携带杂合PROKR2突变（p.R85C、p.Y113H、p.V115M、p.R164Q、p.L173R、p.W178S、p.S188L、p.R248Q、p.V331M和p.R357W）。其中，6 名患有 KS，4 名 nIHH，1 名 KS 先证者同时携带 PROKR2 (p. V115M) 和 PROK2 (p. A24P) 突变。生殖表型范围从缺乏到部分青春期，再到停止治疗后 GnRH 缺乏的完全逆转。所有突变等位基因似乎都会减少细胞内钙的动员；七种表现出 MAPK 信号传导减少，六种表现出受体表达减少。非生殖表型包括纤维发育不良、睡眠障碍、联动症和癫痫。最后，具有相同突变的家庭成员（包括无症状携带者）存在相当大的变异性。结论：PROK2 和 PROKR2 的功能丧失突变是 KS 和 nIHH 的基础。
Context: Mice deficient in prokineticin 2 (PROK2) and prokineticin receptor 2 (PROKR2) exhibit variable olfactory bulb dysgenesis and GnRH neuronal migration defects reminiscent of human GnRH deficiency.Objectives: We aimed to screen a large cohort of patients with Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (IHH) for mutations in PROK2/PROKR2, evaluate their prevalence, define the genotype/phenotype relationship, and assess the functionality of these mutant alleles in vitro.Design: Sequencing of the PROK2 and PROKR2 genes was performed in 170 KS patients and 154 nIHH. Mutations were examined using early growth response 1-luciferase assays in HEK 293 cells and aequorin assays in Chinese hamster ovary cells.Results: Four heterozygous and one homozygous PROK2 mutation (p. A24P, p. C34Y, p. I50M, p. R73C, and p. I55fsX1) were identified in five probands. Four probands had KS and one nIHH, and all had absent puberty. Each mutant peptide impaired receptor signaling in vitro except the I50M. There were 11 patients who carried a heterozygous PROKR2 mutation (p. R85C, p. Y113H, p. V115M, p. R164Q, p. L173R, p. W178S, p. S188L, p. R248Q, p. V331M, and p. R357W). Among them, six had KS, four nIHH, and one KS proband carried both a PROKR2 (p. V115M) and PROK2 (p. A24P) mutation. Reproductive phenotypes ranged from absent to partial puberty to complete reversal of GnRH deficiency after discontinuation of therapy. All mutant alleles appear to decrease intracellular calcium mobilization; seven exhibited decreased MAPK signaling, and six displayed decreased receptor expression. Nonreproductive phenotypes included fibrous dysplasia, sleep disorder, synkinesia, and epilepsy. Finally, considerable variability was evident in family members with the same mutation, including asymptomatic carriers.Conclusion: Loss-of-function mutations in PROK2 and PROKR2 underlie both KS and nIHH.