An ancestral haplotype defines susceptibility to doxorubicin nephropathy in the laboratory mouse.
Haplotype analysis was used to refine of the DOXNPH locus, which harbors the susceptibility gene for doxorubicin (DOX; Adriamycin) nephropathy, a Mendelian form of selective podocyte injury. Analysis of haplotype structure in three strains with contrasting susceptibility (148 single-nucleotide polymorphisms at 101-kb spacing) was complementary to analysis of recombinants in 176 F2 mice. For example, haplotype analysis but not meiotic mapping could exclude the Abcc1 multidrug transporter, and this was confirmed further by phenotypic evaluation of Abcc1 null mice. Next, comparison of haplotype structure (55 single-nucleotide polymorphisms at 44-kb spacing) with phenotype in 15 inbred strains revealed a risk haplotype that was shared by susceptible strains (P = 0.00017), thereby reducing the DOXNPH region to a 1.3-Mb interval. These data demonstrate that susceptibility to DOX nephropathy represents a founder mutation in the laboratory mouse. Haplotype analysis can be used for identification of the DOXNPH gene and prediction of strain susceptibility pattern.
Zheng
Zongyu
Z
Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Pavlidis
Paul
P
Chua
Streamson
S
D'Agati
Vivette D
VD
Gharavi
Ali G
AG
D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity*; D018432:Drug Resistance, Multiple / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D050199:Podocytes / Q000473:pathology; D020641:Polymorphism, Single Nucleotide
D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C492376:Abcc5 protein, mouse; C421109:multidrug resistance-associated protein 1