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DLG2 variants in patients with pubertal disorders
Youn Hee Jee1, Sehoon Won2, Julian C Lui1
1Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Summary
Genetic variants in DLG2/PSD-93 cause delayed puberty and isolated hypogonadotropic hypogonadism (IHH). This occurs through impaired NMDA receptor signaling, leading to reduced gonadotropin-releasing hormone (GnRH) secretion.
Area of Science:
- Endocrinology
- Neuroscience
- Genetics
Background:
- Gonadotropin-releasing hormone (GnRH) neuron dysfunction leads to delayed puberty and isolated hypogonadotropic hypogonadism (IHH).
- Identifying novel genetic causes is crucial for understanding these conditions.
Purpose of the Study:
- To identify a new genetic etiology for delayed puberty and IHH.
- Investigate the role of DLG2/PSD-93 in GnRH neuron function.
Main Methods:
- Exome sequencing in a family with autosomal dominant delayed puberty.
- In vitro studies of a DLG2 variant in a GnRH neuronal cell line.
- Screening of DLG2 in a cohort of individuals with IHH.
Main Results:
- A rare DLG2 (PSD-93) missense variant (F900V) cosegregated with delayed puberty.
- The F900V variant reduced GnRH expression and impaired PSD-93 interaction with Fyn, affecting NMDA receptor signaling.
- DLG2 variants causing reduced GnRH expression were found in three families with IHH.
Conclusions:
- DLG2/PSD-93 variants are a cause of autosomal dominant delayed puberty and may contribute to IHH.
- Pathogenesis involves impaired NMDA receptor signaling and decreased GnRH secretion.
- This highlights PSD-93's role in regulating GnRH neuron function and pubertal timing.
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