title: IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty.
abstract: 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‡.
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Sasha R
authors.initials: SR
authors.lastname: Howard
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Guasti
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Gerard
authors.initials: G
authors.lastname: Ruiz-Babot
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mancini
authors.affiliation: Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London, UK.
authors.forename: Alessia
authors.initials: A
authors.lastname: David
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Storr
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Lousie A
authors.initials: LA
authors.lastname: Metherell
authors.affiliation: Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London, UK.
authors.forename: Michael Je
authors.initials: MJ
authors.lastname: Sternberg
authors.affiliation: Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK.
authors.forename: Claudia P
authors.initials: CP
authors.lastname: Cabrera
authors.affiliation: NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Warren
authors.affiliation: Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Barnes
authors.affiliation: Institute of Genetic Medicine University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Quinton
authors.affiliation: Unité Mixte de Recherche 1141, Institut National de la Santé et de la Recherche Médicale, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France Laboratoire de Biochimie, Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: de Roux
authors.affiliation: Univ Paris-Sud, Le Kremlin Bicêtre, France INSERM UMR-1185, Le Kremlin Bicêtre, France Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin-Bicêtre, France Department of Reproductive Endocrinology, Bicêtre Hospital, Le Kremlin-Bicêtre, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.affiliation: Univ Paris-Sud, Le Kremlin Bicêtre, France INSERM UMR-1185, Le Kremlin Bicêtre, France Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin-Bicêtre, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Guiochon-Mantel
authors.affiliation: Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Karoliina
authors.initials: K
authors.lastname: Wehkalampi
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: André
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences and Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Gothilf
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy Institute of Ophthalmology, University College London (UCL), London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Cariboni
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK l.dunkel@qmul.ac.uk.
authors.forename: Leo
authors.identifier: 0000-0003-4008-8521
authors.initials: L
authors.lastname: Dunkel
mesh_terms: D000293:Adolescent; D000818:Animals; D002465:Cell Movement; D004252:DNA Mutational Analysis; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000166:cytology; D007136:Immunoglobulins / Q000235:genetics*; D008297:Male; D023421:Models, Animal; D050505:Mutant Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D011628:Puberty, Delayed / Q000503:physiopathology*; D017422:Sequence Analysis, DNA; D015027:Zebrafish
chemical_list: C000622854:IGSF10 protein, human; D007136:Immunoglobulins; D050505:Mutant Proteins; D007987:Gonadotropin-Releasing Hormone
keywords: GnRH; delayed puberty; hypothalamic amenorrhea; neuronal migration; puberty