TY - JOUR
T1 - Congenic Mapping of Alcohol and Pentobarbital Withdrawal Liability Loci to a <1 Centimorgan Interval of Murine Chromosome 4
T2 - Identification of Mpdz as a Candidate Gene
AU - Fehr, Christoph
AU - Shirley, Renee L.
AU - Belknap, John K.
AU - Crabbe, John C.
AU - Buck, Kari J.
PY - 2002/5/1
Y1 - 2002/5/1
N2 - 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.
AB - 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.
KW - Barbiturate
KW - C57BL/6J
KW - Convulsion
KW - DBA/2J
KW - Ethanol
KW - Interval-specific congenic strain
KW - PDZ domain
KW - Physiological dependence
KW - Quantitative trait locus
KW - Recombinant progeny testing
KW - Seizure
UR - http://www.scopus.com/inward/record.url?scp=0036584950&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036584950&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.22-09-03730.2002
DO - 10.1523/jneurosci.22-09-03730.2002
M3 - Article
C2 - 11978849
AN - SCOPUS:0036584950
SN - 0270-6474
VL - 22
SP - 3730
EP - 3738
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 9
ER -