Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism
Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism
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DOI：
10.1073/pnas.0707173104
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发表时间：
2007-10-30
影响因子：
11.1
通讯作者：
Crowley, William F., Jr.
中科院分区：
文献类型：
--
作者：
Pitteloud, Nelly;Zhang, Chengkang;Crowley, William F., Jr.
人类促性腺激素释放激素 (GnRH) 缺乏症表现为渗透压正常的特发性低促性腺激素性性腺功能减退症 (nIHH) 或嗅觉丧失症 [卡尔曼综合征 (KS)]。迄今为止，已经确定了几个导致这些疾病的位点，但只有 30% 的病例表现出已知基因的突变。最近，小鼠研究表明前动力蛋白通路在嗅球形态发生和 GnRH 分泌中发挥着关键作用。因此，我们假设前动力蛋白 2 (PROK2) 的突变是人类某些 KS 病例的基础，而缺乏 Prok2 的动物将出现促性腺激素减退。对 100 名没有已知突变的 IHH 先证者（50 nIHH 和 50 KS）进行了 PROK2 基因突变检查。在功能研究中检查了突变的 PROK2，并且还研究了 Prok2(-/-) 小鼠的生殖表型。患有 KS 的两个兄弟和患有 nIHH 的妹妹在 PROK2 基因中存在纯合缺失 (p.[155fsX1]+[155fsX1])。另一个无症状的兄弟是杂合子缺失，而父母（已故）都有正常的生殖史。鉴定出的缺失导致 PROK2 蛋白被截短，含有 27 个氨基酸（而不是成熟形式的 81 个氨基酸），缺乏生物活性。此外，嗅球缺陷的Prok2(-/-)小鼠表现出GnRH神经元迁移中断，导致下丘脑中GnRH神经元数量急剧减少以及性腺功能减退。纯合性 PROK2 功能丧失突变可导致 KS 和 nIHH。
Gonadotropin-releasing hormone (GnRH) deficiency in the human presents either as normosmic idiopathic hypogonadotropic hypogonadism (nIHH) or with anosmia [Kallmann syndrome (KS)]. To date, several loci have been identified to cause these disorders, but only 30% of cases exhibit mutations in known genes. Recently, murine studies have demonstrated a critical role of the prokineticin pathway in olfactory bulb morphogenesis and GnRH secretion. Therefore, we hypothesize that mutations in prokineticin 2 (PROK2) underlie some cases of KS in humans and that animals deficient in Prok2 would be hypogonadotropic. One hundred IHH probands (50 nIHH and 50 KS) with no known mutations were examined for mutations in the PROK2 gene. Mutant PROK2s were examined in functional studies, and the reproductive phenotype of the Prok2(-/-) mice was also investigated. Two brothers with KS and their sister with nIHH harbored a homozygous deletion in the PROK2 gene (p.[155fsX1]+[155fsX1]). Another asymptomatic brother was heterozygous for the deletion, whereas both parents (deceased) had normal reproductive histories. The identified deletion results in a truncated PROK2 protein of 27 amino acids (rather than 81 in its mature form) that lacks bioactivity. In addition, Prok2(-/-) mice with olfactory bulb defects exhibited disrupted GnRH neuron migration, resulting in a dramatic decrease in GnRH neuron population in the hypothalamus as well as hypogonadotropic hypogonadism. Homozygous loss-of-function PROK2 mutations cause both KS and nIHH.