Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age
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 d...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
20 October 2022
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| In: |
Frontiers in medicine
Year: 2022, Jahrgang: 9, Pages: 1-12 |
| ISSN: | 2296-858X |
| DOI: | 10.3389/fmed.2022.953643 |
| Online-Zugang: | Resolving-System, kostenfrei, Volltext: https://doi.org/10.3389/fmed.2022.953643 Verlag, kostenfrei, Volltext: https://www.frontiersin.org/articles/10.3389/fmed.2022.953643 
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| Verfasserangaben: | Roman Günthner, Lea Knipping, Stefanie Jeruschke, Robin Satanoskij, Bettina Lorenz-Depiereux, Clara Hemmer, Matthias C. Braunisch, Korbinian M. Riedhammer, Jasmina Ćomić, Burkhard Tönshoff, Velibor Tasic, Nora Abazi-Emini, Valbona Nushi-Stavileci, Karin Buiting, Nikola Gjorgjievski, Ana Momirovska, Ludwig Patzer, Martin Kirschstein, Oliver Gross, Adrian Lungu, Stefanie Weber, Lutz Renders, Uwe Heemann, Thomas Meitinger, Anja K. Büscher and Julia Hoefele on behalf of the German Pediatric Nephrology (GPN) Study Group |
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| 245 | 1 | 0 | |a Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age |c Roman Günthner, Lea Knipping, Stefanie Jeruschke, Robin Satanoskij, Bettina Lorenz-Depiereux, Clara Hemmer, Matthias C. Braunisch, Korbinian M. Riedhammer, Jasmina Ćomić, Burkhard Tönshoff, Velibor Tasic, Nora Abazi-Emini, Valbona Nushi-Stavileci, Karin Buiting, Nikola Gjorgjievski, Ana Momirovska, Ludwig Patzer, Martin Kirschstein, Oliver Gross, Adrian Lungu, Stefanie Weber, Lutz Renders, Uwe Heemann, Thomas Meitinger, Anja K. Büscher and Julia Hoefele on behalf of the German Pediatric Nephrology (GPN) Study Group |
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| 520 | |a 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. | ||
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| 700 | 1 | |a Patzer, Ludwig |e VerfasserIn |4 aut | |
| 700 | 1 | |a Kirschstein, Martin |e VerfasserIn |4 aut | |
| 700 | 1 | |a Gross, Oliver |e VerfasserIn |4 aut | |
| 700 | 1 | |a Lungu, Adrian |e VerfasserIn |4 aut | |
| 700 | 1 | |a Weber, Stefanie |e VerfasserIn |4 aut | |
| 700 | 1 | |a Renders, Lutz |e VerfasserIn |4 aut | |
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