Cq2^KK
QTL Variant Detail

Summary

• QTL variant: Cq2^KK
• Name: cholesterol QTL 2; KK
• MGI ID: MGI:2153951
• QTL: Cq2 Location: Chr1:174456299-174456436 bp Genetic Position: Chr1, cM position of peak correlated region/allele: 81.08 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: KK

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased plasma cholesterol levels compared to C57BL/6J. (J:54322)
• Inheritance: Dominant

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

Candidate Genes

J:99474

Linkage analysis was performed on 3 separate F2 crosses in 3 previous studies: J: 54322, J:87328 and J:94251 to map QTLs associated with plasma cholesterol levels. Cq1, Cq2, and Cq6 mapped to mouse Chromosome 1, Cq3 mapped to mouse Chromosome 3, and Cq4 and Cq5 mapped to mouse Chromosome 9.

Cq2 and Cq6 map to the same location on distal mouse Chromosome 1 at approximately 100 cM. Cq2 was identified in a (C57BL/6J x KK-A^y)F2 intercross and Cq6 was identified in a (C57BL/6J x RR)F2 intercross. Apoa2 wasinvestigated as a possible candidate gene. The Apoa2^b allele is found in KK and RR strains and is associated with increased cholesterol levels while inbred strain C57BL/6J carries the Apoa2^a allele. It is thought that the Apoa2^b allele may be responsible for the QTL effects of Cq2 and Cq6.

Inbred strains A/J and SM/J carry the Apoa2^c allele. It was previously unknown whether the Apoa2^a and Apoa2^c alleles had the same or different influences on plasma cholesterol level. An F2 intercross between congenic strains C57BL/6J-Apoa2^a and C57BL/6J-Apoa2^c revealed no physiological differences between the Apoa2^a and Apoa2^c alleles. Therefore, the Apoa2^b allele confers increased plasma cholesterol compared to the Apoa2^a and Apoa2^c alleles.

Cq4 and Cq5 map to the same location on mouse Chromosome 9 at approximately 27 cM and Apoa1 and Apoa4 were investigated as possible candidate genes. Cq4 was identified in a (C57BL/6J x KK-A^y)F2 intercross and Cq5 was identified in a (KK x RR)F2 intercross. Sequence analysis of Apoa1 revealed that polymorphic differences between the involved strains did not correlate to cholesterol phenotype. Analysis of Apoa4 revealed a silent polymorphism (C771T) that exhibits complete correlation to cholesterol phenotype. Inbred strain KK carries the T allele whereas inbred strain C57BL/6J and RR carry the C allele. Another polymorphism in Apoa4 was detected involving a 12 nucleotide insertion encoding Glu-Gln-Ala/Val-Gln. Inbred strain KK carries 3 repeats, inbred strain C57BL/6J carries 4 repeats, and inbred strain RR carries 5 repeats. However, it could not be determined if this particular polymorphism explains the QTL effect of Cq4 and Cq5 on cholesterol levels.

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

J:54322

95 microsatellite markers at an average density of 14.4-16.5 cM were used to map loci affecting obesity-associated plasma lipid concentrations in 190 (C57BL/6J x KK-Ay)F2 animals. KK-Ay animals develop severe obesity and elevated plasma lipid concentrations while C57BL/6J remain lean with lower lipid levels. F2 animals of genotype a/a at the agouti locus have an intermediate plasma cholesterol phenotype while F2 animals of genotype Ay/a have a plasma cholesterol phenotype resembling the KK-Ay parental strain.

Three QTLs involved in plasma cholesterol concentrations were identified: Cq1 (LOD = 4.6) and Cq2 (LOD = 5) are linked to D1Mit425 and D1Mit150, respectively, on mouse chromosome 1, and Cq3 (LOD = 4.3) is linked to D3Mit102 on chromosome 3.

Cq2 in linkage with D1Mit150 maps to within 1.1 cM of the Apoa2 locus. Sequencing of Apoa2 cDNA in C57BL/6J and KK revealed 7 nucleotide substitutions (resulting in 3 amino acid substitutions) within the open reading frame.

Nq1 (LOD = 4.3), a QTL involved in plasma NEFA (non-esterified fatty acids) concentrations, mapped to chromosome 9 in association with D9Mit353.

References

• Original: J:54322 Suto J, et al., Quantitative trait loci that regulate plasma lipid concentration in hereditary obese KK and KK-Ay mice. Biochim Biophys Acta. 1999 Mar 30;1453(3):385-95
• All: 1 reference(s)