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DLG2 variants in patients with pubertal disorders

Lookup NU author(s): Professor Timothy Cheetham, Dr Richard Quinton

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Abstract

© 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply. Purpose: Impaired function of gonadotropin-releasing hormone (GnRH) neurons can cause a phenotypic spectrum ranging from delayed puberty to isolated hypogonadotropic hypogonadism (IHH). We sought to identify a new genetic etiology for these conditions. Methods: Exome sequencing was performed in an extended family with autosomal dominant, markedly delayed puberty. The effects of the variant were studied in a GnRH neuronal cell line. Variants in the same gene were sought in a large cohort of individuals with IHH. Results: We identified a rare missense variant (F900V) in DLG2 (which encodes PSD-93) that cosegregated with the delayed puberty. The variant decreased GnRH expression in vitro. PSD-93 is an anchoring protein of NMDA receptors, a type of glutamate receptor that has been implicated in the control of puberty in laboratory animals. The F900V variant impaired the interaction between PSD-93 and a known binding partner, Fyn, which phosphorylates NMDA receptors. Variants in DLG2 that also decreased GnRH expression were identified in three unrelated families with IHH. Conclusion: The findings indicate that variants in DLG2/PSD-93 cause autosomal dominant delayed puberty and may also contribute to IHH. The findings also suggest that the pathogenesis involves impaired NMDA receptor signaling and consequently decreased GnRH secretion.

Publication metadata

Author(s): Jee YH, Won S, Lui JC, Jennings M, Whalen P, Yue S, Temnycky AG, Barnes KM, Cheetham T, Boden MG, Radovick S, Quinton R, Leschek EW, Aguilera G, Yanovski JA, Seminara SB, Crowley WF, Delaney A, Roche KW, Baron J

Publication type: Article

Publication status: Published

Journal: Genetics in Medicine

Year: 2020

Volume: 22

Pages: 1329-1337

Print publication date: 01/08/2020

Online publication date: 28/04/2020

Acceptance date: 31/03/2020

ISSN (print): 1098-3600

ISSN (electronic): 1530-0366

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41436-020-0803-8

DOI: 10.1038/s41436-020-0803-8

PubMed id: 32341572

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