This report describes characterization of the fly alcohol response using the Drosophila gene Efa6. Dmel\Efa6 is a member of a family of guanine nucleotide exchange factors that sustain activation of Arf family GTPases (ArfGEFs); it is orthologous to 4 genes in human, PSD, PSD2, PSD3, and PSD4. RNAi targeting constructs, alleles caused by insertional mutagenesis, and amorphic alleles created by targeted recombination have been generated for Dmel\Efa6.
Ethanol-naive Efa6 loss-of-function mutants are sensitive to ethanol-induced sedation and lack rapid tolerance upon re-exposure to ethanol, when compared with wild-type flies; Efa6 mutants also prefer alcohol-containing food without prior ethanol experience.
These findings led to assessment of the human orthologs of Dmel\Efa6, PSD, PSD2, PSD3, and PSD4, in the context of alcohol-induced behaviors. A SNP (single nucleotide polymorphism) near the PSD3 gene (rs13265422) was found to be associated with behaviors within the spectrum of alcohol use disorder. One of the other human PSD genes, Hsap\PSD4 has been introduced into flies, but has not been characterized.
See also the human disease model report 'alcohol, response to, ARF6-related' (FBhh0000690).
[updated Jul. 2018 by FlyBase; FBrf0222196]
Alcoholism can be defined as persistence of excessive drinking over a long period of time despite adverse health effects and disruption of social relations (Morozova et al., 2014; pubmed:24395673).
The 2013 Diagnostic and Statistical Manual of Mental Disorders (DSM) combined the two former categorizations of abnormal alcohol use (alcohol abuse and alcohol dependence) into one diagnosis: alcohol use disorder. The severity of an individual's AUD is broken into classifications: mild, moderate, or severe. "Alcoholism" is a non-medical term often used to describe a severe form of alcohol use disorder. (https://www.therecoveryvillage.com/recovery-blog/alcoholism-alcohol-use-disorder-whats-difference/)
Excessive alcohol consumption is associated with increased risk of different types of cancer, higher cardiovascular disease mortality, birth defects, liver diseases, and neuropsychiatric disorders (Morozova et al., 2014; pubmed:24395673).
Alcoholism is a multifactorial, genetically influenced disorder. [from MIM:103780; 2017.12.19]
PSD3 encodes 'pleckstrin and Sec7 domain containing 3' which functions as a guanine nucleotide exchange factor for ARF6 (ADP-ribosylation factor 6). [Gene Cards, PSD3, PSD; 2018.07.25]
The protein encoded by ARF6 is a GTP-binding protein that is localized to the plasma membrane and regulates vesicular trafficking, remodelling of membrane lipids, and signaling pathways that lead to actin remodeling. [Gene Cards, ARF6; 2018.01.08]
Many to one: 4 human to 1 Drosophila.
Many to one: 4 human to 1 Drosophila.
Many to one: 4 human to 1 Drosophila.
Many to one: 4 human to 1 Drosophila.
Moderate-scoring ortholog of human PSD, PSD2, PSD3, and PSD4 (1 Drosophila to 4 human). Dmel\Efa6 shares 31-36% identity and 44-49% similarity with PSD, PSD2, and PSD3; it is less closely related to PSD4.
