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 Fehr, Renee L. Shirley, John K. Belknap, John C. Crabbe, Kari J. Buck

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3730-3738
Number of pages9
JournalJournal of Neuroscience
Volume22
Issue number9
DOIs
StatePublished - May 1 2002

Keywords

  • Barbiturate
  • C57BL/6J
  • Convulsion
  • DBA/2J
  • Ethanol
  • Interval-specific congenic strain
  • PDZ domain
  • Physiological dependence
  • Quantitative trait locus
  • Recombinant progeny testing
  • Seizure

ASJC Scopus subject areas

  • Neuroscience(all)

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