Skts13^{M. spretus}
QTL Variant Detail

Summary

• QTL variant: Skts13^{M. spretus}
• Name: skin tumor sucseptibility 13; M. spretus
• MGI ID: MGI:3055776
• QTL: Skts13 Location: Chr2:168623533-172405326 bp Genetic Position: Chr2, Syntenic

Variant origin

• Strain of Specimen: M. spretus

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers resistance to skin tumorigenesis compared to NIH/Ola. (J:84842)
• Inheritance: Not Specified

Notes

Candidate Genes

J:91636

The QTL interval of Skts13 (skin tumor susceptibility 13) shows synteny to a region of human Chromosome 20q13.2 associated with various tumors such as breast, ovarian, and colon tumors. Skts13 was previously identified in a series of backcrosses involving NIH/Ola, M. spretus, SEG/Pas, and SPRET/EI. A search for candidate genes was performed for the Skts13 interval and one gene, Skt6 (100 cM on mouse Chromosome 2), was found to exhibit differential expression between M. musculus and M. Spretus. In the orthologous human gene, SKT6, a polymorphism exists that is associated with increased risk for breast and prostate cancer. In addition, a large proportion of heterozygous colon tumors carry multiple copies of the disease-associated allele in humans.

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

J:84842

Linkage analysis to skin tumor resistance was performed on a previously constructed backcross between M. spretus and NIH/Ola. Parental strain M. spretus is resistant to skin tumor development whereas parental strain NIH/Ola is susceptible. High resolution mapping was performed on 326 (NIH/Ola x M. spretus)F1 x NIH/Ola backcross animals. A papilloma resistance locus named Skts13 was identified on distal mouse Chromosome 2. This region is syntenic to human Chromosome 20q13.2.

Linkage analysis was performed on two additional backcross populations: 106 animals from a (NIH/Ola x SEG/Pas)F1 x NIH/Ola backcross and 163 animals from a (NIH/Ola x SPRET/EiJ)F1 x NIH/Ola backcross. Strong linkage to papilloma resistance was observed at Stks13 in the SPRET/EiJ x NIH/Ola backross (P= 3.7 x 10-5, LOD=4.8). No linkage to papilloma resistance was observed in the NIH/Ola x SEG/Pas backcross.

Haplotype analysis refined the Skts13 resistance interval to a 1 cM region between D2Mit229 (99 cM) and D2Jau1 (100 cM). D2Jau1 refers to a CA3 repeat sequence located 8.1 kb distal of the 5' end of Stk6 and is shown in the same location as D2Mit198. The peakLOD score at this interval is 6.1. Potential candidate genes identified in the Stks13 interval are Cyp24a1 (99 cM), Stk6 (100 cM), and Zfp217 (99 cM). Gene expression analysis of mouse skin tumor mRNA revealed differential expression of Stk6 and Zfp217 but not Cyp24a1. Gene expression analysis of normal mouse skin mRNA revealed increased Stk6 expression in NIH/Ola compared to M. spretus. Zpf217 did not show differential expression in normal mouse skin mRNA between NIH/Ola and M. spretus. Sequence analysisof Stk6 failed to identify polymorphisms between the 2 parental strains. The human ortholog STK6 at 20q13.2 contains a polymorphism at amino acid 31 that may be associated with human cancers.

References

• Original: J:84842 Ewart-Toland A, et al., Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human. Nat Genet. 2003 Aug;34(4):403-12
• All: 1 reference(s)