Mutant mouse reveals potential genetic pathway for alcoholism

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 UCSF. The study appears in the August 12, 2010, edition of “PLoS Genetics.” 

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 observation 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 these genes in humans before,” notes Speca. “There’s a chance that they are part of a new and relatively unexplored biochemical pathway that may tell us something about human susceptibility to alcoholism.” 

Co-authors of the study were Daisuke Chihara, Amir M. Ashique, M. Scott Bowers, Jonathan T. Pierce-Shimomura, and Jungsoo Lee of the Gallo Center and UCSF; Nusrat Rabbee and Terence P. Speed of the University of California, Berkeley; Rodrigo J.  Gularte, James Chitwood, and Juan F. Medrano of the University of California, Davis; Mark Liao, James M. Sonner, and Edmond I. Eger II of UCSF; and principal investigators Andrew S. Peterson, PhD, and Steven L. McIntire, MD, PhD, of the Gallo Center and UCSF (all author affiliations current at the time of the study).

The UCSF-affiliated Ernest Gallo Clinic and Research Center is one of the world’s preeminent academic centers for the study of the biological basis of alcohol and substance use disorders. Gallo Center discoveries of potential molecular targets for the development of therapeutic medications are extended through preclinical and proof-of-concept clinical studies.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.