IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty

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• 作者：Sasha R Howard ; Leonardo Guasti ; Gerard Ruiz-Babot ; Alessandra Mancini ; Alessia David ; Helen L Storr ; Lousie A Metherell ; Michael JE Sternberg ; Claudia P Cabrera ; Helen R Warren ; Michael R Barnes ; Richard Quinton ; Nicolas de Roux ; Jacques Young ; Anne Guiochon-Mantel ; Karoliina Wehkalampi ; Valentina Andr&#233 ; Yoav Gothilf ; Anna Cariboni and Leo Dunkel
• 刊名：EMBO Molecular Medicine
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：8
• 期：6
• 页码：626-642
• 全文大小：2441K
• ISSN：1757-4684

文摘

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.