title: Genetic and Informatic Analyses Implicate Kif12 as a Candidate Gene within the Mpkd2 Locus That Modulates Renal Cystic Disease Severity in the Cys1cpk Mouse.
abstract: We have previously mapped the interval on Chromosome 4 for a major polycystic kidney disease modifier (Mpkd) of the B6(Cg)-Cys1cpk/J mouse model of recessive polycystic kidney disease (PKD). Informatic analyses predicted that this interval contains at least three individual renal cystic disease severity-modulating loci (Mpkd1-3). In the current study, we provide further validation of these predicted effects using a congenic mouse line carrying the entire CAST/EiJ (CAST)-derived Mpkd1-3 interval on the C57BL/6J background. We have also generated a derivative congenic line with a refined CAST-derived Mpkd1-2 interval and demonstrated its dominantly-acting disease-modulating effects (e.g., 4.2-fold increase in total cyst area; p<0.001). The relative strength of these effects allowed the use of recombinants from these crosses to fine map the Mpkd2 effects to a <14 Mbp interval that contains 92 RefSeq sequences. One of them corresponds to the previously described positional Mpkd2 candidate gene, Kif12. Among the positional Mpkd2 candidates, only expression of Kif12 correlates strongly with the expression pattern of Cys1 across multiple anatomical nephron structures and developmental time points. Also, we demonstrate that Kif12 encodes a primary cilium-associated protein. Together, these data provide genetic and informatic validation of the predicted renal cystic disease-modulating effects of Mpkd1-3 loci and implicate Kif12 as the candidate locus for Mpkd2.
authors: Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, United States of America; Department of Veterans Affairs Medical Center, Birmingham, AL 35233, United States of America.
authors: Michal
authors: M
authors: Mrug
authors: Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, United States of America.
authors: Juling
authors: J
authors: Zhou
authors: Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, United States of America; Center for Translational Science, Children's National Health System, Washington, DC 20010, United States of America.
authors: Chaozhe
authors: C
authors: Yang
authors: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 35229, United States of America.
authors: Bruce J
authors: BJ
authors: Aronow
authors: Department of Biostatistics, The University of Alabama at Birmingham, Birmingham, AL 35294, United States of America.
authors: Xiangqin
authors: X
authors: Cui
authors: Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, United States of America.
authors: Trenton R
authors: TR
authors: Schoeb
authors: Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294, United States of America.
authors: Gene P
authors: GP
authors: Siegal
authors: Department of Cell, Developmental and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, United States of America.
authors: Bradley K
authors: BK
authors: Yoder
authors: Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, United States of America; Center for Translational Science, Children's National Health System, Washington, DC 20010, United States of America.
authors: Lisa M
authors: LM
authors: Guay-Woodford
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000737:chemistry*; D019295:Computational Biology; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D056426:Genetic Loci; D005838:Genotype; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058977:Molecular Sequence Annotation; D009399:Nephrons / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017044:Polycystic Kidney, Autosomal Recessive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index
chemical_list: C449819:Cys1 protein, mouse; C503459:KIF12 protein, mouse; D008565:Membrane Proteins; D016547:Kinesins