Open AccessIGSF 10 mutations dysregulate gonadotropin‐releasing hormone neuronal migration resulting in delayed puberty
Author(s) -
Howard Sasha R,
Guasti Leonardo,
RuizBabot Gerard,
Mancini Alessandra,
David Alessia,
Storr Helen L,
Metherell Lousie A,
Sternberg Michael JE,
Cabrera Claudia P,
Warren Helen R,
Barnes Michael R,
Quinton Richard,
Roux Nicolas,
Young Jacques,
GuiochonMantel Anne,
Wehkalampi Karoliina,
André Valentina,
Gothilf Yoav,
Cariboni Anna,
Dunkel Leo
Publication year - 2016
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201606250
Subject(s) - gonadotropin releasing hormone , hormone , endocrinology , medicine , gonadotropin , biology , microbiology and biotechnology , neuroscience , luteinizing hormone
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 IGSF 10 in 6 unrelated families, which resulted in intracellular retention with failure in the secretion of mutant proteins. IGSF 10 mRNA was strongly expressed in embryonic nasal mesenchyme, during gonadotropin‐releasing hormone (Gn RH ) neuronal migration to the hypothalamus. IGSF 10 knockdown caused a reduced migration of immature Gn RH neurons in vitro , and perturbed migration and extension of Gn RH neurons in a gnrh3: EGFP zebrafish model. Additionally, loss‐of‐function mutations in IGSF 10 were identified in hypothalamic amenorrhea patients. Our evidence strongly suggests that mutations in IGSF 10 cause DP in humans, and points to a common genetic basis for conditions of functional hypogonadotropic hypogonadism ( HH ). While dysregulation of Gn RH neuronal migration is known to cause permanent HH , this is the first time that this has been demonstrated as a causal mechanism in DP .