Dxmod
QTL Variant Detail

Summary

• QTL variant: Dxmod
• Name: doxorubicin nephropathy modifier; Doxmod
• MGI ID: MGI:3574893
• QTL: Dxmod Location: Chr9:49452421-101406120 bp Genetic Position: Chr9, Syntenic

Variant origin

• Strain of Specimen: BALB/cJ

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: The BALB/cJ allele modifies dxnph by enhancing doxirubicin nephropathy severity and disease progression by up to 30%. (J:96632)
• Inheritance: Recessive

Notes

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

J:96632

Linkage analysis was performed to identify loci associated with susceptibility to doxorubicin(DOX)-induced nephropathy. Genome scan was performed using 62 polymorphic markers and 308 (BALB/cJ x C57BL/6J)F1 x BALB/cJ backcross animals. Parental strain BALB/cJ is susceptible to DOX-induced nephropathy compared to parental strain C57BL/6J. Significant linkage mapped to an interval on mouse Chromosome 16 between D16Mit154 (3.4 cM) and D16Mit157 (34.1 cM) with LOD=92.7. This region corresponds to 16A1-B1 and is named dxnph (doxorubicin nephropathy). Homozygosity for BALB/c-derived alleles at dxnph confer susceptibility to proteinuria and glomerulosclerosis after DOX injection. dxnph also shows strong linkage to Prmt7 expression, a molecular marker for nephropathy (LOD=11.4 at D16Mit34). BALB/cJ-derived alleles at dxnph confer attenuated Prmt7 expression after DOX injection.

Dxnph was confirmed in a (BALB/cJ x FVB/NJ)F1 x BALB/cJ backcross. Parental strain FVB/NJ is resistant to DOX-induced nephropathy similar to C57BL/6J. Linkage to DOX-induced nephropathy was detected on the same region of mouse Chromosome 16 in this backcross with LOD=5.4. FVB/NJ-derived alleles confer resistance to DOX-induced nephropathy at dxnph.

(BALB/cJ x 129X1/SvJ)F1 hybrids exhibitsusceptibility to DOX-induced nephropathy as expected because parental strain 129X1/SvJ is a susceptible strain. (BALB/cJ x 129X1/SvJ)F1 hybrids were crossed to (BALB/cJ x C57BL/6J)F1 hybrids and dxnph was again confirmed. Animals homozygous for BALB/cJ-derived alleles or heterozygous for BALB/cJ and 129X1SvJ-derived alleles at dxnph exhibit susceptibility to DOX-induced nephropathy (LOD=11.4).

A modifier of dxnph was identified by a second genome scan using 112 polymorphic markers and nephropathy-affected (BALB/cJ x C57BL/6J)F1 x BALB/cJ backcross mice. Linkage to histopathology scores mapped to mouse Chromosome 9 with LOD=4.3. Suggestive linkage to blood urea nitrogen (BUN) was also detected. This locus is named Dxmod (doxorubicin nephropathy modifier)and is confined to an interval between D9Mit229 (28 cM) and D9Mit182 (55 cM). Homozygosity for BALB/cJ-derived alleles at Dxmod confers a 30% increase in histopathology scores. This locus influences the severity and progression of DOX-induced nephropathy. Dxmod overlaps with a previously identified renal failure QTL named Renf1 at 43 cM.

References

• Original: J:96632 Zheng Z, et al., A Mendelian locus on chromosome 16 determines susceptibility to doxorubicin nephropathy in the mouse. Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2502-7
• All: 1 reference(s)