Aabpr^NZB/Slc
QTL Variant Detail

Summary

• QTL variant: Aabpr^NZB/Slc
• Name: aberrant activation of B cell proliferation; NZB/Slc
• MGI ID: MGI:3042398
• QTL: Aabpr Location: Chr2:116033229-122207534 bp Genetic Position: Chr2, cM position of peak correlated region/allele: 58.52 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: NZB/NSlc

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased peripheral B1 cell proliferation compared to NZW/Slc. (J:87690)

Notes

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

J:87690

Genome scan at a resolution of 10 cM was performed on 261 (NZB/Slc x NZW/Slc)F1 x NZB/Slc backcross animals to identify QTLs associated with the aberrant proliferation of peripheral B1 cells, a phenotype associated with systemic lupus erythematosus. Parental strain NZB/Slc exhibits high frequencies of B1 cell activation in conjunction with IgM hypergammaglobulinemia compared to parental strain NZW/Slc.

Abpr (aberrant B cell proliferation) mapped to 65.5 cM on mouse Chromosome 2 (LOD=3.56) spanning the flanking markers D2Mit254 and D2Mit30 [Fig 2]. NZB/Slc-derived alleles confer increased activation of self-reactive B1 cells at this locus.

Several candidate genes map near Abpr and include Ltk (67 cM), Plcb2 (67 cM), Tyro3 (67.1 cM), and B2m (69 cM). Sequence analysis of Ltk revealed a single nucleotide polymorphism (SNP) between NZB/Slc and NZW/Slc strains at nucleotide 1517 (NZB/Slc=A, NZW/Slc=G). This SNP translates to a glutamic acid to glycine amino acid substitution at residue 746 in the kinase domain. When the SNP is typed for linkage to B cell proliferation the LOD score increases to 4.80. The SNP also shows linkage to serum IgM levels (LOD=3.13). Studies with human SLE patients showed correlation of the 746K allele to disease. Ltk is considered a strong candidate gene by the authors.

Functional assays involving the mouse and human Ltk 746K alleles suggested a role of this variant in upregulating the P13K pathway.

References

• Original: J:87690 Li N, et al., Gain-of-function polymorphism in mouse and human Ltk: implications for the pathogenesis of systemic lupus erythematosus. Hum Mol Genet. 2004 Jan 15;13(2):171-9
• All: 1 reference(s)