Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age
Journal
Frontiers in Medicine
Date Issued
2022
Author(s)
Günthner, Roman
Knipping, Lea
Jeruschke, Stefanie
Satanoskij, Robin
Lorenz-Depiereux, Bettina
Hemmer, Clara
Braunisch, Matthias C
Riedhammer, Korbinian M
Ćomić, Jasmina
Tönshoff, Burkhard
Abazi-Emini, Nora
Nushi-Stavileci, Valbona
Buiting, Karin
Momirovska, Ana
Patzer, Ludwig
Kirschstein, Martin
Gross, Oliver
Lungu, Adrian
Weber, Stefanie
Renders, Lutz
Heemann, Uwe
Meitinger, Thomas
Büscher, Anja K
Hoefele, Julia
DOI
10.3389/fmed.2022.953643
Abstract
X-linked Alport syndrome (AS) caused by hemizygous disease-causing variants in COL4A5 primarily affects males. Females with a heterozygous state show a diverse phenotypic spectrum ranging from microscopic hematuria to end-stage kidney disease (ESKD) and extrarenal manifestations. In other X-linked diseases, skewed X-inactivation leads to preferential silencing of one X-chromosome and thus can determine the phenotype in females. We aimed to show a correlation between X-inactivation in blood and urine-derived renal cells and clinical phenotype of females with a heterozygous disease-causing variant in COL4A5 compared to healthy controls. A total of 56 females with a heterozygous disease-causing COL4A5 variant and a mean age of 31.6 ± 18.3 SD years were included in this study. A total of 94% had hematuria, 62% proteinuria >200 mg/day, yet only 7% had decreased eGFR. Using human androgen receptor assay X-inactivation was examined in blood cells of all 56 individuals, in urine-derived cells of 27 of these individuals and in all healthy controls. X-inactivation did not correlate with age of first manifestation, proteinuria or eGFR neither in blood, nor in urine. The degree of X-inactivation showed a moderate association with age, especially in urine-derived cells of the patient cohort (rho = 0.403, p = 0.037). Determination of X-inactivation allelity revealed a shift of X-inactivation toward the COL4A5 variant bearing allele. This is the first study examining X-inactivation of urine-derived cells from female individuals with AS. A correlation between phenotype and X-inactivation could not be observed suspecting other genetic modifiers shaping the phenotype in female individuals with AS. The association of X-inactivation with age in urine-derived cells suggests an escape-mechanism inactivating the COL4A5 variant carrying allele in female individuals with AS.