IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty.
IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty.
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DOI：
10.15252/emmm.201606250
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发表时间：
2016-06
影响因子：
11.1
通讯作者：
Dunkel L
中科院分区：
文献类型：
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作者：
Howard SR;Guasti L;Ruiz-Babot G;Mancini A;David A;Storr HL;Metherell LA;Sternberg MJ;Cabrera CP;Warren HR;Barnes MR;Quinton R;de Roux N;Young J;Guiochon-Mantel A;Wehkalampi K;André V;Gothilf Y;Cariboni A;Dunkel L
青春期早期或晚期发作影响多达5%的青少年，并与不良的健康和心理社会后果有关。自限性青春期延迟（DP）主要以常染色体显性模式分离，但潜在的遗传背景尚不清楚。使用外显子组和候选基因测序，我们已经确定了6个不相关的家庭中IGSF 10的罕见突变，导致细胞内滞留与突变蛋白分泌失败。在促性腺激素释放激素（GnRH）神经元迁移至下丘脑期间，IGSF10 mRNA在胚胎鼻间充质中强烈表达。IGSF10敲低导致体外未成熟GnRH神经元迁移减少，并在gnrh3：EGFP斑马鱼模型中扰乱GnRH神经元的迁移和延伸。此外，在下丘脑性闭经患者中发现了IGSF10的功能缺失突变。我们的证据有力地表明IGSF10突变导致人类DP，并指出功能性低促性腺激素性性腺功能减退症（HH）的共同遗传基础。虽然已知GnRH神经元迁移的失调会导致永久性HH，但这是首次证明这是DP的因果机制。
Early or late pubertal onset affects up to 5% of adolescents and is associated with adverse health and psychosocial outcomes. Self‐limited delayed puberty (DP) segregates predominantly in an autosomal dominant pattern, but the underlying genetic background is unknown. Using exome and candidate gene sequencing, we have identified rare mutations in IGSF10 in 6 unrelated families, which resulted in intracellular retention with failure in the secretion of mutant proteins. IGSF10 mRNA was strongly expressed in embryonic nasal mesenchyme, during gonadotropin‐releasing hormone (GnRH) neuronal migration to the hypothalamus. IGSF10 knockdown caused a reduced migration of immature GnRH neurons in vitro, and perturbed migration and extension of GnRH neurons in a gnrh3:EGFP zebrafish model. Additionally, loss‐of‐function mutations in IGSF10 were identified in hypothalamic amenorrhea patients. Our evidence strongly suggests that mutations in IGSF10 cause DP in humans, and points to a common genetic basis for conditions of functional hypogonadotropic hypogonadism (HH). While dysregulation of GnRH neuronal migration is known to cause permanent HH, this is the first time that this has been demonstrated as a causal mechanism in DP.‡