Gad2, which encodes GAD65, is crucial for the synthesis of GABA in presynaptic terminals for vesicle release. GABA is the major inhibitory neurotransmitter in the adult mammalian brain, involved in normal brain development, and has been linked to various brain functions and neurological diseases [1,4].

Gad2 has been associated with multiple disease conditions. The GAD65 antibody, a biomarker of autoimmune CNS disorders, is related to Gad2-encoded GAD65. Disorders like type 1 diabetes, autoimmune thyroid disease, and pernicious anemia often co-exist with GAD65 neurological autoimmunity [2]. GAD2 is a highly specific marker for pancreatic neuroendocrine neoplasms, which can help identify the pancreatic origin of neuroendocrine neoplasms with unknown sites of origin [3]. In the human prefrontal cortex, alternative transcripts of GAD2 are important in the growth of GABA-synthesizing neurons and abnormal GABA signaling in schizophrenia and affective disorders [4]. While GAD1 polymorphisms are associated with heroin addiction phenotypes, GAD2 polymorphisms show no significant associations [5]. GAD2 on chromosome 10p12 is a candidate gene for human obesity, as its variants are related to eating behaviors, weight gain, and insulin-related parameters [6,7]. Polymorphisms in GAD2 are also associated with methamphetamine dependence in the Thai population [8]. Anti-GAD65 antibodies are related to both acute/subacute seizures and chronic isolated epilepsy, yet the efficacy and prognosis of patients with GAD65-epilepsy are poor [9].

In conclusion, Gad2 is essential for GABA synthesis, playing a significant role in various biological and disease processes, including autoimmune disorders, cancer diagnosis, neurological and psychiatric diseases, addiction, obesity, and epilepsy. Understanding Gad2 through genetic models can provide insights into these disease mechanisms, potentially leading to new treatment strategies.