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

• Published in: Nephrology, dialysis, transplantation Vol. 25; no. 3; pp. 764 - 769
• Main Authors: Rheault, Michelle N., Kren, Stefan M., Hartich, Linda A., Wall, Melanie, Thomas, William, Mesa, Hector A., Avner, Philip, Lees, George E., Kashtan, Clifford E., Segal, Yoav
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-03-2010
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; animal; Animals; Biological and medical sciences; Blood Urea Nitrogen; Clinical Nephrology; collagen type IV; Collagen Type IV - genetics; disease models; Disease Models, Animal; Emergency and intensive care: renal failure. Dialysis management; Female; Genotype; hereditary; Heterozygote; Intensive care medicine; longevity; Male; Medical sciences; Mice; Mice, Congenic; Mice, Inbred C57BL; nephritis; Nephritis, Hereditary - genetics; Nephritis, Hereditary - metabolism; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Phenotype; Proteinuria - urine; Renal failure; Severity of Illness Index; X Chromosome Inactivation - genetics; longevity; nephritis, hereditary; disease models, animal; collagen type IV; female; Glomerulonephritis; Kidney disease; Urinary system disease; Hemodialysis; Collagen type IV; Rodentia; Longevity; Inactivation; disease models; Genetic disease; nephritis; Extrarenal dialysis; Vertebrata; Mammalia; Mouse; Animal; Renal failure; Alport syndrome; hereditary
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfp551

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.