DLG2 variants in patients with pubertal disorders

• Published in: Genetics in medicine Vol. 22; no. 8; pp. 1329 - 1337
• Main Authors: Jee, Youn Hee, Won, Sehoon, Lui, Julian C., Jennings, Melissa, Whalen, Philip, Yue, Shanna, Temnycky, Adrian G., Barnes, Kevin M., Cheetham, Tim, Boden, Matthew G., Radovick, Sally, Quinton, Richard, Leschek, Ellen W., Aguilera, Greti, Yanovski, Jack A., Seminara, Stephanie B., Crowley, William F., Delaney, Angela, Roche, Katherine W., Baron, Jeffrey
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-08-2020; Elsevier Limited
• Subjects: Biomedical and Life Sciences; Biomedicine; Child development; Childrens health; Etiology; Families & family life; Genes; Genomics; Gonadotropin-Releasing Hormone - genetics; Guanylate Kinases; Hospitals; Human Genetics; Humans; Hypogonadism - genetics; Hypothalamus; Kinases; Laboratory animals; Laboratory Medicine; Mass spectrometry; Medical research; Mutagenesis; Neurological disorders; Pathogenesis; Proteins; Puberty; Scientific imaging; Signal Transduction; Tumor Suppressor Proteins; Whole Exome Sequencing; PSD-93; puberty; NMDA receptors; hypogonadotropic hypogonadism; DLG2
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1038/s41436-020-0803-8

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.