BSPED2015 ORAL COMMUNICATIONS Oral Communications 5 (10 abstracts)
Mutations in IGSF10 cause self-limited delayed puberty
Sasha Howard 1 , Leonardo Guasti 1 , Gerard Ruiz-Babot 1 , Alessandra Mancini 1 , Alessia David 2 , Helen Storr 1 , Louise Metherell 1 , Claudia Cabrera 3 , Helen Warren 4 , Michael Barnes 3 , Karoliina Wehkalampi 5 , Yoav Gothilf 6 , Valentina André 7 , Anna Cariboni 7 & Leo Dunkel 1
1Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Centre for Endocrinology, Queen Mary University of London, London, UK; 2Department of Life Sciences, Imperial College London, Centre for Integrative Systems Biology and Bioinformatics, London, UK; 3Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Centre for Translational Bioinformatics, Queen Mary University of London, London, UK; 4Department of Clinical Pharmacology, Barts and The London School of Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK; 5Children’s Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; 6Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel; 7Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
Background: Abnormal pubertal timing affects over 4% of adolescents and is associated with adverse health and psychosocial outcomes. Previous studies estimate that 60–80% of variation in the timing of pubertal onset is genetically determined. However, despite this strong heritability, little is known about the genetic control of human puberty. Self-limited delayed puberty (DP) segregates in an autosomal dominant pattern, but in the majority of patients the neuroendocrine pathophysiology and its genetic regulation remain unclear.
Methods: We performed whole exome sequencing in 52 members of seven families from our patient cohort with DP, with follow-up targeted re-sequencing of candidate genes in a further 42 families. The functional consequences of the identified mutations in one candidate gene were interrogated via expression of WT and mutant proteins in mammalian cells. For this gene we defined tissue expression in human and mouse embryos by in situ hybridization and immunohistochemistry. The effects of gene knockdown were investigated via in vitro neuronal migration assays, and in vivo using a transgenic zebrafish model with fluorescently labeled GnRH neurons.
Results: We identified four rare mutations in IGSF10 in ten unrelated families, which are tightly associated with the DP trait within our cohort (P=3.47×10−4). The identified mutations are in evolutionarily conserved positions, and two mutations result in intracellular retention with failure in secretion of the N-terminal fragment of the protein. IGSF10 mRNA is strongly expressed in the nasal mesenchyme in mouse and human embryos, during the time-period when GnRH neurons migrate from their nasal origin towards the hypothalamus. IGSF10 knockdown caused reduced migration of immature GnRH neurons in the in vitro analysis, and perturbed migration and extension of GnRH neurons in the zebrafish model.
Conclusions: We present our novel finding that mutations in IGSF10 cause delayed puberty in humans, through misregulation of GnRH neuronal migration during embryonic development.
Volume 39
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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