Age- and tissue-specific variation of X-inactivation ratios in X-linked Alport syndrome females

Hongwen Zhang, Jie Ding, Fang Wang
Department of Pediatrics, Peking University First Hospital, Beijing, People's Republic of China

Background: Alport syndrome (AS) is a progressive renal disease characterized by hematuria and progressive renal failure. X-linked dominant AS (XLAS) is the major inheritance form, accounting for almost 80% of the cases. XLAS females have variable phenotypes, from microscopic hematuria to chronic renal failure. These variable phenotypes cannot be clarified solely by mutation features of the COL4A5 gene. X-inactivation has been suspected to be one of the reasons responsible for this phenomenon, but so far definite correlation has not been demonstrated. Moreover, it was supposed that X-inactivation ratios may vary both with age and between different tissues within an individual. This study analyzed the age- and tissue-specific variation of X-inactivation ratios in XLAS females.
Methods: Peripheral blood cells were collected from 36 XLAS females, and cultured skin fibroblasts were collected from 12 of them. The X-inactivation analysis was performed using HpaII predigestion of DNA followed by polymerase chain reaction (PCR) of the highly polymorphic CAG repeat of the androgen receptor (AR) gene.
Results: The rate of heterozygosity at the AR locus of the 36 female patients was 88.89%. Only 12.50% (4/32) of females detected showed skewed X-inactivation in peripheral blood cells. No individual under 30 years of age had skewed X-inactivation, and 20% (4/20) of individuals over 30 years of age had skewed X-inactivation in peripheral blood cells (χ2 = 2.743, P = 0.098). The X-inactivation patterns of the 12 patients showed marked variation between blood cells and skin fibroblasts. Seven of the 12 patients (58.33%) had similar X-inactivation ratios in both tissues, but the other 5 patients (41.67%) had the opposite X-inactivation ratios in both tissues. There was no correlation between the X-inactivation ratios of the mutant allele in skin fibroblasts and in peripheral blood cells (r = 0.180, P = 0.575).
Conclusion: There was no age-specific variation of X-inactivation ratios in XLAS females but there was tissue-specific variation, which maybe could explain the contradictory results between X-inactivation and the variable phenotype of XLAS females.

Keywords: Alport syndrome, female, X-inactivation