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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9630586/ https://www.ncbi.nlm.nih.gov/pubmed/36341250 http://dx.doi.org/10.3389/fmed.2022.953643 |
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author | Günthner, Roman Knipping, Lea Jeruschke, Stefanie Satanoskij, Robin Lorenz-Depiereux, Bettina Hemmer, Clara Braunisch, Matthias C. Riedhammer, Korbinian M. Ćomić, Jasmina Tönshoff, Burkhard Tasic, Velibor Abazi-Emini, Nora Nushi-Stavileci, Valbona Buiting, Karin Gjorgjievski, Nikola Momirovska, Ana Patzer, Ludwig Kirschstein, Martin Gross, Oliver Lungu, Adrian Weber, Stefanie Renders, Lutz Heemann, Uwe Meitinger, Thomas Büscher, Anja K. Hoefele, Julia |
author_facet | Günthner, Roman Knipping, Lea Jeruschke, Stefanie Satanoskij, Robin Lorenz-Depiereux, Bettina Hemmer, Clara Braunisch, Matthias C. Riedhammer, Korbinian M. Ćomić, Jasmina Tönshoff, Burkhard Tasic, Velibor Abazi-Emini, Nora Nushi-Stavileci, Valbona Buiting, Karin Gjorgjievski, Nikola Momirovska, Ana Patzer, Ludwig Kirschstein, Martin Gross, Oliver Lungu, Adrian Weber, Stefanie Renders, Lutz Heemann, Uwe Meitinger, Thomas Büscher, Anja K. Hoefele, Julia |
author_sort | Günthner, Roman |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9630586 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-96305862022-11-04 Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age Günthner, Roman Knipping, Lea Jeruschke, Stefanie Satanoskij, Robin Lorenz-Depiereux, Bettina Hemmer, Clara Braunisch, Matthias C. Riedhammer, Korbinian M. Ćomić, Jasmina Tönshoff, Burkhard Tasic, Velibor Abazi-Emini, Nora Nushi-Stavileci, Valbona Buiting, Karin Gjorgjievski, Nikola Momirovska, Ana Patzer, Ludwig Kirschstein, Martin Gross, Oliver Lungu, Adrian Weber, Stefanie Renders, Lutz Heemann, Uwe Meitinger, Thomas Büscher, Anja K. Hoefele, Julia Front Med (Lausanne) Medicine 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. Frontiers Media S.A. 2022-10-20 /pmc/articles/PMC9630586/ /pubmed/36341250 http://dx.doi.org/10.3389/fmed.2022.953643 Text en Copyright © 2022 Günthner, Knipping, Jeruschke, Satanoskij, Lorenz-Depiereux, Hemmer, Braunisch, Riedhammer, Ćomić, Tönshoff, Tasic, Abazi-Emini, Nushi-Stavileci, Buiting, Gjorgjievski, Momirovska, Patzer, Kirschstein, Gross, Lungu, Weber, Renders, Heemann, Meitinger, Büscher and Hoefele. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Medicine Günthner, Roman Knipping, Lea Jeruschke, Stefanie Satanoskij, Robin Lorenz-Depiereux, Bettina Hemmer, Clara Braunisch, Matthias C. Riedhammer, Korbinian M. Ćomić, Jasmina Tönshoff, Burkhard Tasic, Velibor Abazi-Emini, Nora Nushi-Stavileci, Valbona Buiting, Karin Gjorgjievski, Nikola Momirovska, Ana Patzer, Ludwig Kirschstein, Martin Gross, Oliver Lungu, Adrian Weber, Stefanie Renders, Lutz Heemann, Uwe Meitinger, Thomas Büscher, Anja K. Hoefele, Julia Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age |
title | Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age |
title_full | Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age |
title_fullStr | Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age |
title_full_unstemmed | Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age |
title_short | Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age |
title_sort | renal x-inactivation in female individuals with x-linked alport syndrome primarily determined by age |
topic | Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9630586/ https://www.ncbi.nlm.nih.gov/pubmed/36341250 http://dx.doi.org/10.3389/fmed.2022.953643 |
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