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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
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.
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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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