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 candid...
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Springer Nature
2016-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201606250 |
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| author | 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 André Yoav Gothilf Anna Cariboni Leo Dunkel |
| author_facet | 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 André Yoav Gothilf Anna Cariboni Leo Dunkel |
| author_sort | Sasha R Howard |
| collection | DOAJ |
| description | 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.‡ |
| format | Article |
| id | doaj-art-b88afcd856224f63a71e372f61a45f58 |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-b88afcd856224f63a71e372f61a45f582025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-04-018662664210.15252/emmm.201606250IGSF10 mutations dysregulate gonadotropin‐releasing hormone neuronal migration resulting in delayed pubertySasha R Howard0Leonardo Guasti1Gerard Ruiz‐Babot2Alessandra Mancini3Alessia David4Helen L Storr5Lousie A Metherell6Michael JE Sternberg7Claudia P Cabrera8Helen R Warren9Michael R Barnes10Richard Quinton11Nicolas de Roux12Jacques Young13Anne Guiochon‐Mantel14Karoliina Wehkalampi15Valentina André16Yoav Gothilf17Anna Cariboni18Leo Dunkel19Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of LondonCentre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of LondonCentre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of LondonCentre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of LondonCentre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College LondonCentre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of LondonCentre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of LondonCentre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College LondonCentre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of LondonNIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of LondonCentre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of LondonInstitute of Genetic Medicine University of Newcastle‐upon‐TyneUnité Mixte de Recherche 1141, Institut National de la Santé et de la Recherche MédicaleUniv Paris‐SudUniv Paris‐SudChildren's Hospital, Helsinki University Hospital and University of HelsinkiDepartment of Pharmacological and Biomolecular Sciences, University of MilanDepartment of Neurobiology, The George S. Wise Faculty of Life Sciences and Sagol School of Neuroscience, Tel‐Aviv UniversityDepartment of Pharmacological and Biomolecular Sciences, University of MilanCentre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of LondonAbstract 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.‡https://doi.org/10.15252/emmm.201606250delayed pubertyGnRHhypothalamic amenorrheaneuronal migrationpuberty |
| spellingShingle | 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 André Yoav Gothilf Anna Cariboni Leo Dunkel IGSF10 mutations dysregulate gonadotropin‐releasing hormone neuronal migration resulting in delayed puberty EMBO Molecular Medicine delayed puberty GnRH hypothalamic amenorrhea neuronal migration puberty |
| title | IGSF10 mutations dysregulate gonadotropin‐releasing hormone neuronal migration resulting in delayed puberty |
| title_full | IGSF10 mutations dysregulate gonadotropin‐releasing hormone neuronal migration resulting in delayed puberty |
| title_fullStr | IGSF10 mutations dysregulate gonadotropin‐releasing hormone neuronal migration resulting in delayed puberty |
| title_full_unstemmed | IGSF10 mutations dysregulate gonadotropin‐releasing hormone neuronal migration resulting in delayed puberty |
| title_short | IGSF10 mutations dysregulate gonadotropin‐releasing hormone neuronal migration resulting in delayed puberty |
| title_sort | igsf10 mutations dysregulate gonadotropin releasing hormone neuronal migration resulting in delayed puberty |
| topic | delayed puberty GnRH hypothalamic amenorrhea neuronal migration puberty |
| url | https://doi.org/10.15252/emmm.201606250 |
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