Gabra6, encoding the α6 subunit of the γ -aminobutyric acid type A receptor (GABAAR), is crucial for mediating inhibitory neurotransmission in the central nervous system, particularly in the cerebellum [4,5]. GABAARs are involved in multiple physiological and pathological processes, and Gabra6's function contributes to the regulation of neuronal excitability and synaptic plasticity [1,2,5].

Regarding its association with diseases, conflicting results exist. A meta-analysis found no significant association between GABRA6 rs3219151 polymorphism and the risk of epilepsy and antiepileptic drug responsiveness in Asian and Arabic populations [1]. However, in a Pakistani cohort, the GABRA6 rs3219151 was significantly associated with idiopathic generalized epilepsy [2]. Also, in Chinese patients, GABRA6 heterozygosity was associated with functional heartburn [3]. Additionally, a GABRA6 mutation (R46W) identified as a susceptibility gene for childhood absence epilepsy altered GABA(A) receptor channel gating and expression [5]. The T1521C polymorphism in the GABRA6 gene was associated with specific personality characteristics and an attenuated stress response [6], and the T allele of rs3219151 increased current anxiety, depression, and suicide-related risks in those exposed to recent negative life events [7].

In conclusion, Gabra6 plays a vital role in inhibitory neurotransmission and synaptic regulation in the central nervous system. Its genetic variations are associated with various neurological and psychological conditions such as epilepsy, functional heartburn, stress response, and suicide-related risks. Understanding Gabra6's function through genetic models can potentially provide insights into the pathogenesis of these diseases and aid in developing new therapeutic strategies.

References:

1. Zhang, Tiejun, Yang, Yi, Sima, Xiutian. 2022. No association of GABRA1 rs2279020 and GABRA6 rs3219151 polymorphisms with risk of epilepsy and antiepileptic drug responsiveness in Asian and Arabic populations: Evidence from a meta-analysis with trial sequential analysis. In Frontiers in neurology, 13, 996631. doi:10.3389/fneur.2022.996631. https://pubmed.ncbi.nlm.nih.gov/36188399/

2. Riaz, Mehwish, Abbasi, Muddasir Hassan, Sheikh, Nadeem, Saleem, Tayyaba, Virk, Ahmad Omair. 2021. GABRA1 and GABRA6 gene mutations in idiopathic generalized epilepsy patients. In Seizure, 93, 88-94. doi:10.1016/j.seizure.2021.10.013. https://pubmed.ncbi.nlm.nih.gov/34740144/

3. Lee, Yi-Chia, Wang, Hsiu-Po, Chiu, Han-Mo, Lin, Jaw-Town, Wu, Ming-Shiang. . GABRA6 genetic polymorphism is associated with the risk of functional heartburn in Chinese. In Journal of gastroenterology and hepatology, 22, 227-33. doi:. https://pubmed.ncbi.nlm.nih.gov/17295876/

4. Bandesh, Khushdeep, Pal, Muneesh, Balakrishnan, Abitha, Pillai, Beena, Bharadwaj, Dwaipayan. . A novel antisense lncRNA, ARBAG harboring an RNA destabilizing GWAS variant for C-peptide dictates the transcript isoforms of GABRA6 in cerebellum. In Human molecular genetics, 32, 2929-2939. doi:10.1093/hmg/ddad119. https://pubmed.ncbi.nlm.nih.gov/37498167/

5. Hernandez, Ciria C, Gurba, Katharine N, Hu, Ningning, Macdonald, Robert L. 2011. The GABRA6 mutation, R46W, associated with childhood absence epilepsy, alters 6β22 and 6β2 GABA(A) receptor channel gating and expression. In The Journal of physiology, 589, 5857-78. doi:10.1113/jphysiol.2011.218883. https://pubmed.ncbi.nlm.nih.gov/21930603/

6. Uhart, M, McCaul, M E, Oswald, L M, Choi, L, Wand, G S. . GABRA6 gene polymorphism and an attenuated stress response. In Molecular psychiatry, 9, 998-1006. doi:. https://pubmed.ncbi.nlm.nih.gov/15197399/

7. Gonda, Xenia, Sarginson, Jane, Eszlari, Nora, Juhasz, Gabriella, Bagdy, Gyorgy. 2017. A new stress sensor and risk factor for suicide: the T allele of the functional genetic variant in the GABRA6 gene. In Scientific reports, 7, 12887. doi:10.1038/s41598-017-12776-8. https://pubmed.ncbi.nlm.nih.gov/29018204/