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The Journal of Neuroscience, May 1, 2002, 22(9):3730-3738

Congenic Mapping of Alcohol and Pentobarbital Withdrawal Liability Loci to a <1 Centimorgan Interval of Murine Chromosome 4: Identification of Mpdz as a Candidate Gene

Christoph Fehr¹, Renee L. Shirley¹, John K. Belknap^{1, 2}, John C. Crabbe^{1, 2}, and Kari J. Buck¹

¹ Portland Alcohol Research Center and Department of Behavioral Neuroscience, Oregon Health and Science University, and ² Department of Veterans Affairs Medical Center, Portland, Oregon 97201

Risk for onset of alcoholism is related to genetic differences in acute alcohol withdrawal liability. We previously mapped a locus responsible for 26% of the genetic variance in acute alcohol withdrawal convulsion liability to a >35 centimorgan (cM) interval of murine chromosome 4. Here, we narrow the position of this locus to a <1 cM interval (~1.8 megabase, containing 15 genes and/or predicted genes) using a combination of novel, interval-specific congenic strains and recombinant progeny testing. We report the development of a small-donor-segment congenic strain, which confirms capture of a gene affecting alcohol withdrawal within the <1 cM interval. We also confirm a pentobarbital withdrawal locus within this interval, suggesting that the same gene may influence predisposition to physiological dependence on alcohol and a barbiturate. This congenic strain will be invaluable for determining whether this interval also harbors a gene(s) underlying other quantitative trait loci mapped to chromosome 4, including loci affecting voluntary alcohol consumption, alcohol-induced ataxia, physical dependence after chronic alcohol exposure, and seizure response to pentylenetetrazol or an audiogenic stimulus. To date, Mpdz, which encodes the multiple PSD95/DLG/ZO-1 (PDZ) domain protein (MPDZ), is the only gene within the interval shown to have allelic variants that differ in coding sequence and/or expression. Sequence analysis of 15 standard inbred mouse strains identifies six Mpdz haplotypes that predict three MPDZ protein variants. These analyses, and evidence using interval-specific congenic lines, show that alcohol withdrawal severity is genetically correlated with MPDZ status, indicating that MPDZ variants may influence alcohol withdrawal liability.

Key words: quantitative trait locus; recombinant progeny testing; interval-specific congenic strain; PDZ domain; ethanol; barbiturate; physiological dependence; convulsion; seizure; C57BL/6J; DBA/2J

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2293730-09$05.00/0

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