NDT Advance Access published online on October 23, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp551
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
X-inactivation modifies disease severity in female carriers of murine X-linked Alport syndrome
1 Division of Pediatric Nephrology, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA 2 Division of Renal Diseases and Hypertension, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA 3 Minneapolis VA Medical Center, Minneapolis, MN 55417, USA 4 Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA 5 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA 6 Unité de Génétique Moléculaire Murine, Institut Pasteur, 75274 Paris Cedex 15, France 7 Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Texas A & M University, College Station, TX 77483, USA
Correspondence and offprint requests to: Correspondence and offprint requests to: Yoav Segal; E-mail: ysegal{at}umn.edu
 |
Abstract |
|---|
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.
Keywords: collagen type IV; disease models, animal; female; longevity; nephritis, hereditary
Received for publication: 19. 6.09
Accepted in revised form: 22. 9.09