Etax9^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: Etax9^C57BL/6J
• Name: ethanol induced ataxia 9; C57BL/6J
• MGI ID: MGI:3652800
• QTL: Etax9 Location: Chr11:55284985-72209927 bp Genetic Position: Chr11, Syntenic

Variant origin

• Strain of Specimen: C57BL/6J

Variant description

• Allele Type: QTL

Notes

Candidate Genes

J:83912

Candidate genes for alcohol traits were identified using gene expression analysis. Total brain RNA from 10 week old male HAFT1 and LAFT1 (and replicate HAFT2 and LAFT2) mice were hybridized to DNA microarrays to detect differentially expressed genes. HAFT1 and LAFT1 are high and low alcohol functional tolerance (AFT) selection lines, respectively, derived from HS/Ibg. HAFT1 mice display greater alcohol functional tolerance and blood ethanol concentration at time of regaining balance on the dowel test compared to LAFT1 mice. Candidate genes mapping to previously identified AFT QTL intervals are described below. Differential expression of candidate genes was also confirmed using RT-PCR analysis. Promoter sequence analysis of identified candidate genes revealed one or more transcription factor binding sites.

On mouse Chromosome 1, Prdx6 at 83.6 cM was identified as a potential candidate gene for Etax2 (ethanol induced ataxia 2). This gene is expressed in HAFT1 mice at 87% of the mRNA levels in LAFT1 mice (p<0.001). Etax2 is linked to initial blood ethanol concentration (BEC) after dowel test, acute functional tolerance, and BEC after regaining balance.

On mouse Chromosome 2, Grin1 at 12 cM was identified as a potential candidate gene for Etax3 (ethanol induced ataxia 3). This gene isexpressed in HAFT1 mice at 190% of the mRNA levels in LAFT1 mice (p<0.006). Etax3 is linked to acute functional tolerance.

On mouse Chromosome 6, Grid2 at 29.65 cM was identified as a potential candidate gene for Etax6 (ethanol induced ataxia 6). Thisgene is expressed in HAFT1 mice at 139% of the mRNA levels in LAFT1 mice (p<0.006). Etax6 is linked to initial BEC after dowel test and BEC after regaining balance.

On mouse Chromosome 11, Efnb3 at 40 cM, Zfp179 at 34.5 cM, and Skp1a (formerly Tceb1l) at 31 cM were identified as potential candidate genes for Etax9 (ethanol induced ataxia 9). Efnb3 is expressed in HAFT1 mice at 119% of the mRNA levels in LAFT1 (p<0.002). Zfp197 is expressed at in HAFT1 mice at 159% of the mRNA levels in LAFT1 mice (p<0.002), and Skp1a is expressed at in HAFT1 mice at 137% of the mRNA levels in LAFT1 mice (p<0.002). Etax9 is linked to initial BEC after dowel test and BEC after regaining balance.

Mapping and Phenotype information for this QTL, its variants and associated markers

J:78665

Linkage analysis was performed on male animals from 30 BXD (B=C57BL/6J; D=DBA/2J) recombinant inbred (RI) strains to identify QTLs associated with ethanol-induced ataxia and brain cAMP signaling. More than 2000 marker loci were evaluated for linkage. Animals were injected with ethanol and subjected to the dowel balance test. Blood ethanol concentration (BEC) was measured after the first fall off the dowel. Cerebellar cAMP signaling was also measured. Parental strain C57BL/6J exhibits lower BEC and acute functional tolerance (AFT) after dowel test, and decreased cerebellar cAMP accumulation 1 week after behavioral testing, compared to parental strain DBA/2J. Loci reaching statistical significance of p<0.01 are reported.

On mouse Chromosome 1, linkage to initial BEC after dowel test and basal cerebellar cAMP mapped to an interval between D1Byu1 (18.4 cM) and D1Mit76 (32.8 cM). This locus is named Etax1 (ethanol induced ataxia 1). Creb1 (31 cM) is a potential candidate gene near Etax1, however, sequence analysis of the Creb1 coding region did not detect any polymorphisms between C57BL/6J and DBA/2J. Creb1 expression levels also did not differ between C57BL/6J and DBA/2J. Linkage to initial BEC after dowel test, acute functional tolerance, and BEC after regaining balance mapped to an interval between Lamc1 (81.1 cM) and P1Ehs1 (89.2 cM). This locus is named Etax2 (ethanol induced ataxia 2).

On mouse Chromosome 2, linkage to basal cerebellar cAMP mapped to 6.4 cM near Il2ra. This locus is named Ccmp1 (cerebellar cAMP 1). Etax3 (ethanol induced ataxia 3) mapped to 11 cM near D2Mit293, and Etax4 (ethanol induced ataxia 4) mapped to an interval between D2Mit17 (69 cM) and Mpmv28 (71 cM). Etax3 and Etax4 are linked to acute functional tolerance.

On mouse Chromosome 3, linkage to forskolin-induced cerebellar cAMP mapped to 22.7 cM near D3Pas1. Linkage to basal cerebellar cAMP mapped to an interval between Iapls2-9 (47 cM) and Cd53 (48.5 cM). These loci are named Ccmp2 (cerebellar cAMP 2) and Ccmp3 (cerebellarcAMP 3), respectively.

On mouse Chromosome 4, linkage to isoproterenol-induced cerebellar cAMP mapped to an interval between D4Mit178 (35.5 cM) and Typr1 (38 cM). This locus is named Ccmp4 (cerebellar cAMP 4).

On mouse Chromosome 6, linkage to acute functional tolerance and BEC after regaining balance mapped to an interval between D6Rik62 (10 cM) and D6Rik65 (21 cM). This locus is named Etax5 (ethanol induced ataxia 5). Etax6 (ethanol induced ataxia 6) is linked to initial BEC after dowel test and BECafter regaining balance and maps to an interval between D6Mit16 (30.5 cM) and Tgfa (35.8 cM).

On mouse Chromosome 7, linkage to basal cerebellar cAMP mapped to 54 cM near D7Mit7. This locus is named Ccmp5 (cerebellar cAMP 5).

On mouse Chromosome 8, linkage to initial BEC after dowel test and basal cerebellar cAMP mapped to an interval between D8Mit3 (10 cM) and D8Mit191 (21 cM). This locus is named Etax7 (ethanol induced ataxia 7). Ccmp6 (cerebellar cAMP 6) mapped to an interval between Acadm-ps2 (48 cM)and D8Byu6 (56 cM) and is linked to forskolin-induced cerebellar cAMP. A potential candidate gene for Ccmp6 is Adcy7 (40 cM).

On mouse Chromosome 10, linkage to initial BEC after dowel test mapped to 60 cM near Xmv31. This locus is named Etax8 (ethanolinduced ataxia 8).

On mouse Chromosome 11, linkage to basal cerebellar cAMP mapped to an interval between D11Mit62 (1.5 cM) and Pmv22 (8 cM). This locus is named Ccmp7 (cerebellar cAMP 7). Potential candidate genes for Ccmp7 include Adcy1 (1.25 cM) and Camk2b (0.5 cM). Etax9 (ethanol induced ataxia 9) mapped to an interval between Sparc (29.9 cM) and D11Mit219 (43) and Etax10 (ethanol induced ataxia 10) mapped to 71 cM near D11Mit12. Etax9 and Etax10 are both linked to initial BEC after dowel test and BECafter regaining balance. Potential candidate genes for Etax9 include Glra1 (30 cM), Gria (31 cM), Chrnb1 (40 cM), Chrne (42 cM), and Slc6a4 (42 cM).

On mouse Chromosome 14, linkage to acute functional tolerance mapped to 0.5 cM near D14Byu1. This locus isnamed Etax11 (ethanol induced ataxia 11).

On mouse Chromosome 17, linkage to basal and forskolin-induced cerebellar cAMP mapped to an interval between D17Mit49 (23.2 cM) and Stmn1-rs2 (formerly Lag-rs2; 38.9 cM). This locus is named Ccmp8 (cerebellar cAMP8).

On mouse Chromosome 19, linkage to forskolin-induced cerebellar cAMP mapped to an interval between Gnb1-ps1 (0 cM) and D19Mit42 (5 cM). This locus is named Ccmp9 (cerebellar cAMP 9).

References

• Original: J:78665 Kirstein SL, et al., Quantitative trait loci affecting initial sensitivity and acute functional tolerance to ethanol-induced ataxia and brain cAMP signaling in BXD recombinant inbred mice. J Pharmacol Exp Ther. 2002 Sep;302(3):1238-45
• All: 1 reference(s)