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Published ahead of print on February 23, 2005
J Am Soc Nephrol 16: 905-916, 2005
© 2005 American Society of Nephrology
doi: 10.1681/ASN.2004121083
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Genetics and Development

Kinesin Family Member 12 Is a Candidate Polycystic Kidney Disease Modifier in the cpk Mouse

Michal Mrug*, Renhua Li§, Xiangqin Cui§, Trenton R. Schoeb{dagger}, Gary A. Churchill§ and Lisa M. Guay-Woodford*,{dagger},{ddagger}

Departments of * Medicine, {dagger} Genetics, and {ddagger} Pediatrics University of Alabama at Birmingham, Birmingham, Alabama; and § The Jackson Laboratory, Bar Harbor, Maine

Address correspondence to: Dr. Lisa M. Guay-Woodford, Division of Genetic and Translational Medicine, University of Alabama at Birmingham, 740 Kaul Human Genetics Building, 720 20th Street South, Birmingham, AL 35294. Phone: 205-934-7308; Fax: 205-975-5689; E-mail: lgw{at}uab.edu

Received for publication December 14, 2004. Accepted for publication January 5, 2005.

The cpk mouse is the most extensively characterized model of autosomal recessive polycystic kidney disease (ARPKD). The major ARPKD-related renal and biliary phenotypes are modulated in F2 mutants by genetic background, suggesting that quantitative trait loci (QTL) modulate disease severity. In 461 F2 cpk mice, kidney length, weight, and volume were scored as quantitative traits (QT), and a semiquantitative method to assess biliary duct number, area (BDA), portal vein area, and total area of each portal field, as well as the severity of cholangitis, was developed. QTL mapping was performed with Pseudomarker v1.02. Candidate genes were identified within the QTL intervals on the basis of expression profiling, reverse transcriptase–PCR, haplotypes, and sequence analysis. The renal QT were normally distributed in the F2 cohort and strongly correlated (P < 0.001). Among the biliary QT, only BDA correlated with the renal QT (P < 0.01). Genome-wide scan identified a major effect QTL on chromosome (Chr) 4 for the renal traits, adjusted BDA, and cholangitis with logarithm of odds scores of 18, 8, and 5, respectively. Regression modeling refined the Chr 4 main effect into an approximately 50-cM region with three distinct QTL peaks at 16, 34, and 54 cM. Kif12, a gene encoding a novel kinesin, mapped beneath the 34 cM QTL peak and has expression level variants and strain-specific sequences that were associated with renal disease severity in affected mice. Therefore, the positional candidate gene, Kif12, fulfills the major criteria for QTL gene discovery established by the Complex Trait Consortium, and, thus, it is proposed that Kif12 is a cpk modifier gene.




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