ESPE Abstracts (2021) 94 FC8.1

ESPE2021 Free Communications Neuroendocrinology (6 abstracts)

Combined omic analysis revealed autism-linked NLGN3 as new candidate gene associated to GnRH neuron development and disease.

Roberto Oleari 1 , Antonella Lettieri 2,3 , Alyssa Paganoni 1 , Sasha R Howard 4 & Anna Cariboni 1

1Department. Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.;2CRC Aldo Ravelli for Neurotechnology and Experimental Brain Therapeutics, University of Milan, Milan, Italy.;3Dept. Health Sciences, University of Milan, Milan, Italy.;4Centre for Endocrinology, Queen Mary, University of London, London, United Kingdom

During development, gonadotropin releasing hormone (GnRH) neurons are born in the nasal placode and migrate to the hypothalamus, where they position to regulate sexual reproduction by pulsatile release of GnRH. Defective GnRH neuron development or action may lead to GnRH deficiency (GD) which is characterized by absent or delayed puberty. Several GD causative genes have been identified so far, but half of the cases are still idiopathic. The employment of complementary research approaches may be useful to identify additional genes implicated in GD pathogenesis. Here, we combined the transcriptomic analysis of primary and immortalized GnRH neurons with whole exome sequencing data from GD patients to identify novel candidate genes. As a proof-of-principle, we identified pathogenic variants in the autism-linked Neuroligin 3 (NLGN3) gene in patients with severe delayed puberty and autistic traits. We demonstrated that NLGN3 is enriched in GnRH neurons at late developmental stages and its overexpression in a model of immortalized GnRH neurons promoted neurite extension. Complementary to this finding, identified NLGN3 mutations resulted in prematurely truncated proteins which are retained in the endoplasmic reticulum preventing formation of cell protrusions. Overall, our results highlighted how the combination of gene expression and exome sequencing data is a reliable approach to identify novel candidate gene for GD such as NLGN3, an autism-linked gene that we found for the first time associated with GD. These data may also suggest the existence of biological or clinical links between reproductive defects and neurodevelopmental disorders.

Volume 94

59th Annual ESPE (ESPE 2021 Online)

22 Sep 2021 - 26 Sep 2021

European Society for Paediatric Endocrinology 

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