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High-resolution genetic localization of a modifying locus affecting disease severity in the juvenile cystic kidneys (jck) mouse model of polycystic kidney disease
We have previously demonstrated that a locus on proximal Chr 4 modifies disease severity in the juvenile cystic kidney (
jck)
mouse, a model of polycystic kidney disease (PKD) that carries a mutation of the
Nek8
serine-threonine kinase. In this study, we used QTL analysis of independently constructed B6.D2 congenic lines to confirm this and showed that this locus has a highly significant effect. We constructed sub-congenic lines to more specifically localize the modifier and have determined it resides in a 3.2 Mb interval containing 28 genes. These include
Invs
and
Anks6
, which are both excellent candidates for the modifier as mutations in these genes result in PKD and both genes are known to genetically and physically interact with
Nek8
. However, examination of strain-specific DNA sequence and kidney expression did not reveal clear differences that might implicate either gene as a modifier of PKD severity. The fact that our high-resolution analysis did not yield an unambiguous result highlights the challenge of establishing the causality of strain-specific variants as genetic modifiers, and suggests that alternative strategies be considered.