Autism-linked NLGN3 is a key regulator of gonadotropin-releasing hormone deficiency.
Autism spectrum disorder
Delayed puberty
GnRH neurons
NLGN3
Neuritogenesis
Transcriptome
Journal
Disease models & mechanisms
ISSN: 1754-8411
Titre abrégé: Dis Model Mech
Pays: England
ID NLM: 101483332
Informations de publication
Date de publication:
01 03 2023
01 03 2023
Historique:
received:
16
11
2022
accepted:
24
01
2023
medline:
29
3
2023
pubmed:
23
2
2023
entrez:
22
2
2023
Statut:
ppublish
Résumé
Gonadotropin-releasing hormone (GnRH) deficiency (GD) is a disorder characterized by absent or delayed puberty, with largely unknown genetic causes. The purpose of this study was to obtain and exploit gene expression profiles of GnRH neurons during development to unveil novel biological mechanisms and genetic determinants underlying GD. Here, we combined bioinformatic analyses of immortalized and primary embryonic GnRH neuron transcriptomes with exome sequencing from GD patients to identify candidate genes implicated in the pathogenesis of GD. Among differentially expressed and filtered transcripts, we found loss-of-function (LoF) variants of the autism-linked neuroligin 3 (NLGN3) gene in two unrelated patients co-presenting with GD and neurodevelopmental traits. We demonstrated that NLGN3 is upregulated in maturing GnRH neurons and that NLGN3 wild-type, but not mutant, protein promotes neuritogenesis when overexpressed in developing GnRH cells. Our data represent proof of principle that this complementary approach can identify new candidate GD genes and demonstrate that LoF NLGN3 variants can contribute to GD. This novel genotype-phenotype correlation implies common genetic mechanisms underlying neurodevelopmental disorders, such as GD and autistic spectrum disorder.
Identifiants
pubmed: 36810932
pii: 301020
doi: 10.1242/dmm.049996
pmc: PMC10110398
pii:
doi:
Substances chimiques
neuroligin 3
0
Nerve Tissue Proteins
0
Membrane Proteins
0
Gonadotropin-Releasing Hormone
33515-09-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministero della Salute
ID : GR-2016-02362389
Organisme : National Institute for Health and Care Research
ID : CL-2017-19-002
Organisme : Wellcome Trust
ID : 222049/Z/20/Z
Pays : United Kingdom
Organisme : Barts Charity
ID : MGU0552
Organisme : Rosetrees Trust
ID : M222-F1
Organisme : Innovative Medicines Initiative
ID : 777394
Organisme : European Society for Paediatric Endocrinology
Organisme : Collegio Ghislieri di Pavia
Organisme : British Society for Neuroendocrinology
Informations de copyright
© 2023. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing or financial interests.
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