University of California, San Francisco News Office (Aug. 12, 2010) —
A mutation found in a mouse gene that also appears in humans might provide new insights into the genetic roots of alcoholism, according to a study led by researchers at the Ernest Gallo Clinic and Research Center and the University of California, San Francisco.
The researchers found that the mutant mice were dramatically more sensitive to alcohol than their normal, wild-type littermates, and voluntarily consumed more alcohol than normal mice when offered the choice between alcohol and water.
The mutation, which the researchers named Lightweight, is in the mouse version of a gene called unc-79, which previous studies in worms and flies have shown is associated with altered sensitivity to a variety of anesthetics, including alcohol.
Lead author David J. Speca, PhD, who was a Gallo Center researcher at the time the study was conducted, says that the name Lightweight refers to the fact that when unc-79 mutant mice are injected with pure ethanol -- the type of alcohol used in alcoholic beverages -- "they are knocked out for far longer than normal mice."
The function of unc-79 is not well understood, says Speca, but he notes that experiments by other researchers suggest it may interact with a neuron channel (a complex of proteins essential to neuron function) named NALCN to influence neuronal response to alcohol.
Although the current study did not demonstrate an interaction with the NALCN channel in Lightweight mice, Speca says that follow-up experiments in Caenorhabditis elegans, a worm commonly used in biological experiments, showed that the NALCN channel influences responses to alcohol, "suggesting that this response may be conserved from worms to mice to humans."
According to Speca, identifying the factors that make humans susceptible to alcoholism is difficult because of the likelihood that there are multiple genes, each with its own effect, that contribute to the disease. The question now, he says, is whether unc-79 and the NALCN neuron channel turn out to be associated with altered responses to alcohol in humans.
"Nobody has ever studied this channel in humans before," notes Speca. "There's a chance that it's part of a new and relatively unexplored genetic pathway that may tell us something about human susceptibility to alcoholism."
Conserved Role of unc-79 in Ethanol Responses in Lightweight Mutant Mice.
David J. Speca, Daisuke Chihara, Amir M. Ashique, M. Scott Bowers, Jonathan T. Pierce-Shimomura, Jungsoo Lee, Nusrat Rabbee, Terence P. Speed, Rodrigo J. Gularte, James Chitwood, Juan F. Medrano, Mark Liao, James M. Sonner, Edmond I. Eger, II, Andrew S. Peterson Steven L. McIntire
PLoS Genetics, 2010; 6 (8): e1001057 DOI: 10.1371/journal.pgen.1001057
Link to PLoS Genetics abstract