Year: 2022
Type: Article
Title: Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age
Author: Günthner, Roman
Author: Knipping, Lea
Author: Jeruschke, Stefanie
Author: Satanoskij, Robin
Author: Lorenz-Depiereux, Bettina
Author: Hemmer, Clara
Author: Braunisch, Matthias C
Author: Riedhammer, Korbinian M
Author: Ćomić, Jasmina
Author: Tönshoff, Burkhard
Author: Tasic, Velibor
Author: Abazi-Emini, Nora
Author: Nushi-Stavileci, Valbona
Author: Buiting, Karin
Author: Gjorgjievski, Nikola
Author: Momirovska, Ana
Author: Patzer, Ludwig
Author: Kirschstein, Martin
Author: Gross, Oliver
Author: Lungu, Adrian
Author: Weber, Stefanie
Author: Renders, Lutz
Author: Heemann, Uwe
Author: Meitinger, Thomas
Author: Büscher, Anja K
Author: Hoefele, Julia
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.
Publisher: Frontiers Media SA
Relation: Frontiers in Medicine
Identifier: oai:repository.ukim.mk:20.500.12188/24720
Identifier: 2296-858X
Identifier: http://hdl.handle.net/20.500.12188/24720Identifier: 10.3389/fmed.2022.953643
Identifier: https://www.frontiersin.org/articles/10.3389/fmed.2022.953643/fullIdentifier: 9
