GABBR2 gene encodes the GABAB receptor subunit 2 that forms an active heterodimeric GABAB receptor complex with receptor subunit 1. GABAB receptor (GABABR) complex inhibits neuronal activity through GABA signaling at both the presynaptic and postsynaptic membranes, where it regulates neurotransmitter release and the activity of ion channels. Pathogenic variants of GABABR inhibit GABA signaling, responsible for variable phenotypes (epilepsy, epileptic encephalopathy(EE), or Rett-like phenotype(RTT)). The rate of GABA signaling alteration may depend on the location of the variants in the GABABR. For example, pathogenic variants (G693W, S695I, and I705A) associated with Epileptic encephalopathy (EE) are located in the transmembrane domain 6 (TM6) of the GABABR. These variants are more likely to affect the structural integrity of GABBR2 with a substantial reduction of the GABA signaling. In contrast, pathogenic variants (A567T) associated with the Rett-like phenotypes(RTT) are located in the TM3. These variants cause a lesser degree of signaling alternation. Other than the location of the variants, signaling intensity alteration may also be responsible for the phenotype as the TM6 variant with a lesser degree of signaling alternation may cause RTT than EE phenotype. The functional consequence of variants in the extracellular regions is unclear. However, one child with a de novo missense variant in the extracellular domain was reported. He had a milder phenotype (mild developmental delays and absence seizures that remitted at seven years of age) than that reported with variants in the TM regions.
GABBR2