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.
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 (approximately 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.
Fehr
Christoph
C
Portland Alcohol Research Center and Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon 97201, USA.
Shirley
Renee L
RL
Belknap
John K
JK
Crabbe
John C
JC
Buck
Kari J
KJ
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D005796:Genes; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D007178:Inbreeding; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D020297:Mice, Congenic; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D010424:Pentobarbital / Q000009:adverse effects*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index; D012737:Sex Factors; D013375:Substance Withdrawal Syndrome / Q000235:genetics*
D002352:Carrier Proteins; D005819:Genetic Markers; D008565:Membrane Proteins; C491750:Mpdz protein, mouse; D000431:Ethanol; D010424:Pentobarbital