X-inactivation modifies disease severity in female carriers of murine X-linked Alport syndrome.
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.
Rheault
Michelle N
MN
Division of Pediatric Nephrology, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
Kren
Stefan M
SM
Hartich
Linda A
LA
Wall
Melanie
M
Thomas
William
W
Mesa
Hector A
HA
Avner
Philip
P
Lees
George E
GE
Kashtan
Clifford E
CE
Segal
Yoav
Y
D000818:Animals; D001806:Blood Urea Nitrogen; D024141:Collagen Type IV / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D006579:Heterozygote; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D009394:Nephritis, Hereditary / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011507:Proteinuria / Q000652:urine; D012720:Severity of Illness Index; D049951:X Chromosome Inactivation / Q000235:genetics*
C549554:Col4a5 protein, mouse; D024141:Collagen Type IV