Department of Biotechnology, Institute of Sciences, Cukurova University, 01330 Adana, Turkey.
Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
Am J Hum Genet. 2014 Sep 4;95(3):326-31. doi: 10.1016/j.ajhg.2014.08.006.
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.
促性腺激素释放激素（GnRH）神经元起源于中枢神经系统（CNS）外的嗅基板，并迁移到 CNS 中，成为下丘脑-垂体-性腺（HPG）轴的组成部分。这种迁移的破坏会导致 Kallmann 综合征（KS），其特征是由于促性腺激素低下性性腺功能减退导致的嗅觉丧失和青春期失败。我们使用候选基因筛查、自交系作图和全外显子组测序，对 30 名 KS 患者进行了研究，以寻找与 KS 新相关的基因。我们在两个独立的近亲家庭中发现了 FEZF1 的纯合失活突变，每个家庭都有两个受影响的兄弟姐妹。FEZF1 的产物已知可使嗅受体神经元（ORNs）的轴突穿透小鼠的 CNS 基底膜。因为这些轨迹中的一部分轴突是 GnRH 神经元的迁移途径，所以在 FEZF1 缺乏的情况下， GnRH 神经元也无法进入大脑。这些结果表明，FEZF1 对于人类 HPG 轴的中枢成分的建立是必需的。
