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Mutations in FEZF1 cause Kallmann syndrome.
American Journal of Human Genetics ( IF 9.8 ) Pub Date : 2014-09-04 , DOI: 10.1016/j.ajhg.2014.08.006
L Damla Kotan 1 , B Ian Hutchins 2 , Yusuf Ozkan 3 , Fatma Demirel 4 , Hudson Stoner 2 , Paul J Cheng 2 , Ihsan Esen 4 , Fatih Gurbuz 5 , Y Kenan Bicakci 6 , Eda Mengen 5 , Bilgin Yuksel 5 , Susan Wray 2 , A Kemal Topaloglu 7
Affiliation  

Gonadotropin-releasing hormone (GnRH) neurons originate outside the CNS in the olfactory placode and migrate into the CNS, where they become integral components of the hypothalamic-pituitary-gonadal (HPG) axis. Disruption of this migration results in Kallmann syndrome (KS), which is characterized by anosmia and pubertal failure due to hypogonadotropic hypogonadism. Using candidate-gene screening, autozygosity mapping, and whole-exome sequencing in a cohort of 30 individuals with KS, we searched for genes newly associated with KS. We identified homozygous loss-of-function mutations in FEZF1 in two independent consanguineous families each with two affected siblings. The FEZF1 product is known to enable axons of olfactory receptor neurons (ORNs) to penetrate the CNS basal lamina in mice. Because a subset of axons in these tracks is the migratory pathway for GnRH neurons, in FEZF1 deficiency, GnRH neurons also fail to enter the brain. These results indicate that FEZF1 is required for establishment of the central component of the HPG axis in humans.

中文翻译:

FEZF1 突变导致卡尔曼综合征。

促性腺激素释放激素 (GnRH) 神经元起源于中枢神经系统外部的嗅觉基板并迁移到中枢神经系统,在那里它们成为下丘脑 - 垂体 - 性腺 (HPG) 轴的组成部分。这种迁移的中断导致卡尔曼综合征 (KS),其特征是由于低促性腺激素性性腺机能减退导致的嗅觉丧失和青春期衰竭。在 30 名 KS 患者的队列中使用候选基因筛选、自体定位和全外显子组测序,我们搜索了与 KS 新相关的基因。我们在两个独立的近亲家庭中发现了 FEZF1 中的纯合功能丧失突变,每个家庭都有两个受影响的兄弟姐妹。已知 FEZF1 产品使嗅觉受体神经元 (ORN) 的轴突能够穿透小鼠的中枢神经系统基底层。由于这些轨道中的一部分轴突是 GnRH 神经元的迁移途径,因此在 FEZF1 缺陷中,GnRH 神经元也无法进入大脑。这些结果表明 FEZF1 是建立人类 HPG 轴中心成分所必需的。
更新日期:2019-11-01
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