GABBR2, short for Gamma-Aminobutyric acid Type B Receptor Subunit 2, is a gene encoding a subunit of the GABAB receptor. GABAB receptors are G protein-coupled receptors for γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. The GABAergic pathway, in which GABBR2 is involved, is crucial for maintaining the balance between neuronal excitation and inhibition [4,5,6,7].

Mutations in GABBR2 have been associated with multiple neurodevelopmental and neurological disorders. De novo mutations in GABBR2 are linked to early-infantile epileptic encephalopathy (EIEE59), a Rett syndrome (RTT)-like disorder (NDPLHS), and epilepsy. For example, a pediatric case with a de novo GABBR2 pathogenic variant presented with a phenotype encompassing RTT, epilepsy, generalized hypotonia, and paroxysmal limb dystonia [1]. Also, a 7-year-old boy with Level 3 Autism Spectrum Disorder carried a de novo heterozygous missense GABBR2 variant [6]. In addition, in bladder cancer, GABBR2 acts as a downstream effector of the androgen receptor, inducing cisplatin resistance [3]. And in post-ischemic angiogenesis, GABBR2 regulates angiogenesis by inhibiting the glycolysis pathway [2].

In conclusion, GABBR2 plays a vital role in the GABAergic pathway, maintaining the balance of neuronal excitation and inhibition. Its mutations are associated with various neurodevelopmental disorders such as epilepsy, RTT-like disorders, and autism spectrum disorder. Also, it has implications in cancer drug resistance and post-ischemic angiogenesis. The study of GABBR2 using genetic models helps in understanding the pathogenesis of these diseases and may provide potential therapeutic targets.