Search

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations to PKD1 or PKD2, triggering progressive cystogenesis and typically leading to end-stage renal disease in midlife. The phenotypic spectrum, however, ranges from in utero onset to adequate renal function at old age. Recent patient data suggest that the disease is dosage dependent, where incompletely penetrant alleles influence disease severity. Here, we have developed a knockin mouse model matching a likely disease variant, PKD1 p.R3277C (RC), and have proved that its functionally hypomorphic nature modifies the ADPKD phenotype. While Pkd1+/null mice are normal, Pkd1RC/null mice have rapidly progressive disease, and Pkd1RC/RC animals develop gradual cystogenesis. These models effectively mimic the pathophysiological features of in utero-onset and typical ADPKD, respectively, correlating the level of functional Pkdl product with disease severity, highlighting the dosage dependence of cystogenesis. Additionally, molecular analyses identified p.R3277C as a temperature-sensitive folding/ trafficking mutant, and length defects in collecting duct primary cilia, the organelle central to PKD patho-genesis, were clearly detected for the first time to our knowledge in PKD1. Altogether, this study highlights the role that in trans variants at the disease locus can play in phenotypic modification of dominant diseases and provides a truly orthologous PKD1 model, optimal for therapeutic testing. [ABSTRACT FROM AUTHOR]

Mutations in copper/zinc superoxide dismutase (SOD1) account for 10–20% of a familial form of amyotrophic lateral sclerosis (ALS). A common feature of SOD1 mutants is abnormal aggregation of the aberrant SOD1 in neurons and glia. We now report that in ALS transgenic mouse models the constitutively expressed heat shock protein 70 (Hsp70) is mislocalized into aggregates together with mutant SOD1 and ubiquitin. Forcing increased synthesis of Hsp70 ameliorates both aggregate formation and toxicity in primary motor neurons in culture. However, chronic increase in an inducible form of Hsp70 to about 10-fold its normal level is shown here not to affect disease course or pathology developed in mice from accumulation of any of three familial ALS causing SOD1 mutants with different underlying biochemical characteristics. Therefore, increasing Hsp70 to a level that is protective in mouse models of acute ischemic insult and selected neurodegenerative disorders is not sufficient to ameliorate mutant SOD1-mediated toxicity. [ABSTRACT FROM AUTHOR]