ESPE Abstracts (2024) 98 S12.3

ESPE2024 Symposia The impact of gonadotrophin dysregulation on neurocognition (3 abstracts)

Studying the genetic interplay between GnRH deficiency and associated neurocognitive disorders by combining in silico, in vitro and in vivo tools.

Roberto Oleari 1 , Antonella Lettieri 2 , Federica Amoruso 1 , Peter Scheiffele 3 , Sasha Howard 4,5 , Christiana Ruhrberg 6 & Anna Cariboni 1


1Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy. 2Department of Health Sciences, Università degli Studi di Milano, Milan, Italy. 3Biozentrum of the University of Basel, Basel, Switzerland. 4Centre for Endocrinology William Harvey Research Institute Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. 5Department of Paediatric Endocrinology, Barts Health NHS Trust, London, United Kingdom. 6UCL Institute of Ophthalmology, University College London, London, United Kingdom


Gonadotropin releasing hormone (GnRH) neurons embryonically originate in nasal placode and migrate to hypothalamus, where they release GnRH to control reproduction. Defective GnRH neuron development or function leads to GnRH deficiency (GD), which is often associated to neurodevelopmental and neurological syndromes, including epilepsy, ataxia, intellectual disabilities and deafness. In addition, a register-based study showed correlation between delayed puberty and neurodevelopmental disorders. Notably, half of GD cases are still idiopathic and the discovery of novel genetic determinants might be hidden by co-occurrence of GD with severe symptoms in complex diseases. Complementary research approaches may be useful to identify additional genes implicated in the pathogenesis of GD syndromic forms. First, by combining transcriptomic analysis of primary and immortalized GnRH neurons with exome sequencing data from GD patients, we identified nonsense variants in autism-linked gene Neuroligin 3 (NLGN3) in patients exhibiting GD and autistic traits. We showed that NLGN3 expression is higher in GnRH neurons at late developmental stages and demonstrated that overexpression of wildtype NLGN3 in immortalized GnRH neurons promotes neurite extension, whilst mutated forms of NLGN3 are retained in cytoplasm preventing neuritogenesis. Then, we investigated whether Heparan Sulfate 6-O Sulfotransferase 2 (HS6ST2) gene, implicated in a neurodevelopmental disorder, genetically interacts with its paralogue HS6ST1, a known GD gene. We showed Hs6st1 and Hs6st2 enrichment in the olfactory placode and that mice with combined Hs6st1/Hs6st2 deletions have impaired GnRH neuron migration due to aberrant nasal axons and fewer GnRH neurons overall. Consistently, they display increased apoptotic rate of GnRH neurons and defective binding of pro-survival signal VEGF. Overall, we highlighted how the combination of gene expression and exome sequencing data together with in vitro and in vivo models, is a reliable approach to identify novel GD candidate genes, including NLGN3 and HS6ST2, which are already involved in neurological syndromes and represent a link between reproductive and neurodevelopmental disorders.

Volume 98

62nd Annual ESPE (ESPE 2024)

Liverpool, UK
16 Nov 2024 - 18 Nov 2024

European Society for Paediatric Endocrinology 

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