X-inactivation modifies disease severity in female carriers of murine X-linked Alport syndrome

Nephrol Dial Transplant. 2010 Mar;25(3):764-9. doi: 10.1093/ndt/gfp551. Epub 2009 Oct 23.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Urea Nitrogen
  • Collagen Type IV / genetics
  • Disease Models, Animal*
  • Female
  • Genotype
  • Heterozygote
  • Male
  • Mice
  • Mice, Congenic
  • Mice, Inbred C57BL
  • Nephritis, Hereditary / genetics*
  • Nephritis, Hereditary / metabolism
  • Phenotype
  • Proteinuria / urine
  • Severity of Illness Index*
  • X Chromosome Inactivation / genetics*


  • Col4a5 protein, mouse
  • Collagen Type IV