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We have previously mapped the interval on Chromosome 4 for a major polycystic kidney disease modifier ( Mpkd ) of the B6(Cg)- Cys1    cpk  /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 .

plos one

Genetic and Informatic Analyses Implicate Kif12 as a Candidate Gene within the Mpkd2 Locus That Modulates Renal Cystic Disease Severity in the Cys1cpk Mouse