Journal
NEPHROLOGY DIALYSIS TRANSPLANTATION
Volume 25, Issue 3, Pages 764-769Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ndt/gfp551
Keywords
collagen type IV; disease models; animal; female; longevity; nephritis; hereditary
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Funding
- US National Institutes of Health [DK60695, DK64273]
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Methods. Using a genetically defined mouse model of XLAS, we generated two groups of Alport female (Col4a5(+/-)) carriers that differed only in the X-controlling element (Xce) allele regulating X-inactivation. We followed the groups as far as 6 months of age comparing survival and surrogate outcome measures of urine protein and plasma urea nitrogen. Results. Preferential inactivation of the mutant Col4a5 gene improved survival and surrogate outcome measures of urine protein and plasma urea nitrogen. In studies of surviving mice, we found that X-inactivation in kidney, measured by allele-specific mRNA expression assays, correlated with surrogate outcomes. Conclusions. Our findings establish X-inactivation as a major modifier of the carrier phenotype in X-linked Alport syndrome. Thus, X-inactivation patterns may offer prognostic information and point to possible treatment strategies for symptomatic carriers.
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