Background. Female carriers of X-linked Alport syndrome (XLAS) demonstrate variability in clinical phenotype that, unlike males, cannot be correlated with genotype. X-inactivation, the method by which females (XX) silence transcription from one X chromosome in order to achieve gene dosage parity with males (XY), likely modifies the carrier phenotype, but this hypothesis has not been tested directly.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.
Bibliographical noteFunding Information:
Acknowledgements. The authors are grateful to R. Ehlenfeldt for technical assistance and Dr. B. Migeon for comments on a preliminary version of the manuscript. This work was supported by US National Institutes of Health grants DK60695 and DK64273 and with resources and the use of facilities at the Minneapolis VA Medical Center.
- Collagen type IV
- Disease models, animal
- Longevitynephritis, hereditary