This report describes characterization of the fly alcohol response using the Drosophila gene happyhour (hppy). Dmel\hppy is a MAP4K serine/threonine kinase with orthology to four of the six MAP4K genes in human; it is most closely related to MAP4K3 and MAP4K5. RNAi targeting constructs, alleles caused by insertional mutagenesis, and amorphic alleles created by targeted recombination have been generated for Dmel\hppy.
None of the orthologous human MAP4K genes has been introduced into flies.
Animals homozygous for amorphic alleles of Dmel\hppy are viable and fertile. In a genetic screen for mutants with altered sensitivity to ethanol sedation, an allele of hppy exhibited a decrease in ethanol sensitivity (resistance to ethanol-induced sedation); a second allele tested also shows a decreased sensitivity phenotype. Both alleles were determined to result in significantly reduced levels of hppy expression. Pan-neuronal expression of a UAS-hppy using wild-type hppy is able to rescue the decreased sensitivity phenotype. Physical and genetic interactions of Dmel\hppy have been described; see below and in the hppy gene report.
Since MAPKs are known to act via the JNK, p38, and ERK signaling pathways, additional mutations in Drosophila genes within these pathways were assessed for ethanol sensitivity. Only genes within the ERK pathway or the EGFR signaling pathway exhibited a change in sensitivity: activated or overexpressing mutations result in decreased sensitivity; loss-of-function alleles result in increased sensitivity (FBhh0000685). Thus, it is postulated that Dmel\hppy acts to inhibit EGFR-mediated activation of ERK.
[updated Dec. 2017 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]
MAP kinase kinase kinase kinases (MAP4Ks) belong to the mammalian Ste20-like family of serine/threonine kinases. Mitogen-activated protein kinases, including ERK, JNK, and p38, play essential roles in regulating cell activation, proliferation, differentiation, and apoptosis. MAP4Ks have been reported to induce JNK activation via the MAP3K-MAP2K cascade (Chuang et al., 2016; pubmed:26791862).
Many to one: 4 human to 1 Drosophila; the two high-scoring human orthologs are MAP4K3 and MAP4K5.
Many to one: 4 human to 1 Drosophila; the two high-scoring human orthologs are MAP4K3 and MAP4K5.
High-scoring ortholog of human MAP4K3 and MAP4K5; moderate-scoring ortholog of MAP4K1 and MAP4K2 (1 Drosophila to 4 human). Dmel\hppy shares 40-41% identity and 51-52% similarity with the high-scoring human orthologs, MAP4K3 and MAP4K5.
