Endocrine Abstracts (2015) 38 OC1.2 | DOI: 10.1530/endoabs.38.OC1.2

Mutations in IGSF10 cause self-limited delayed puberty, via disturbance of GnRH neuronal migration

Sasha Howard1, Leo Guasti1, Gerard Ruiz-Babot1, Alessandra Mancini1, Alessia David5, Helen Storr1, Louise Metherell1, Michael Sternberg5, Claudia Cabrera2,4, Helen Warren3,4, Michael Barnes2,4, Karoliina Wehkalampi6,7, Valentina André9, Yoav Gothilf8, Anna Cariboni9,10 & Leo Dunkel1

1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 2Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 3Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK; 4NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK; 5Department of Life Sciences, Imperial College London, Centre for Integrative Systems Biology and Bioinformatics, London, UK; 6Children’s Hospital, Helsinki University Hospital, Helsinki, Finland; 7University of Helsinki, Helsinki, Finland; 8Departement of Neurobiology, The George S. Wise Faculty of Life Sciences and Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel; 9Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; 10University College London (UCL), Institute of Ophthalmology, London, UK.

Background: Timing of puberty is associated with height, cardiovascular health and cancer risk, with a significant public health impact. Previous studies estimate that 60–80% of variation in the timing of pubertal onset is genetically determined. Self-limited delayed puberty (DP) segregates in an autosomal dominant pattern, but the underlying genetic background is unknown.

Methods: We performed whole exome sequencing in 111 members of 18 families from our patient cohort with self-limited DP, with follow-up targeted re-sequencing of candidate genes in a further 42 families. For one candidate gene we defined tissue expression in human and mouse embryos. The effects of gene knockdown were investigated via neuronal migration assays, and in vivo using a transgenic zebrafish model with fluorescently-labelled GnRH neurons. N-terminal fragment mutations were interrogated via expression in mammalian cells.

Results: We identified four rare heterozygous variants in IGSF10 in 29 members of ten unrelated families. All four variants were in evolutionarily conserved positions and were predicted by in silico analysis to have a deleterious effect on protein function. Statistical tests showed a significant difference in the prevalence of these mutations within DP cases compared to a general population (P=4.46×10−3), and a significant association between these mutations and the delayed puberty trait within our cohort (P=3.47×10−4). IGSF10 mRNA shows strong expression 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 transgenic zebrafish model. Reduced secretion of mutant protein was demonstrated by western blotting.

Conclusions: We present our novel finding that IGSF10 mutations contribute to the phenotype of self-limited delayed puberty in humans, through impairment of migration of GnRH neurons during embryonic development.