Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age

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; Julia Hoefele

doi:10.3389/fmed.2022.953643

Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age

Front Med (Lausanne). 2022 Oct 20:9:953643. doi: 10.3389/fmed.2022.953643. eCollection 2022.

Authors

Roman Günthner^{1

2}, Lea Knipping³, Stefanie Jeruschke³, Robin Satanoskij¹, Bettina Lorenz-Depiereux⁴, Clara Hemmer², Matthias C Braunisch^{1

2}, Korbinian M Riedhammer^{1

2}, Jasmina Ćomić^{1

2}, Burkhard Tönshoff⁵, Velibor Tasic⁶, Nora Abazi-Emini⁶, Valbona Nushi-Stavileci⁷, Karin Buiting⁸, Nikola Gjorgjievski⁹, Ana Momirovska¹⁰, Ludwig Patzer¹¹, Martin Kirschstein¹², Oliver Gross¹³, Adrian Lungu¹⁴, Stefanie Weber¹⁵, Lutz Renders¹, Uwe Heemann¹, Thomas Meitinger², Anja K Büscher³, Julia Hoefele²

Affiliations

¹ Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany.
² Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany.
³ Pediatric Nephrology, University Hospital Essen, Essen, Germany.
⁴ Molecular Epidemiology, Helmholtz Zentrum München, Munich, Germany.
⁵ Department of Pediatrics I, University Children's Hospital Heidelberg, Heidelberg, Germany.
⁶ University Children's Hospital, Medical Faculty of Skopje, Skopje, North Macedonia.
⁷ Pediatric Clinic, University Clinical Center of Kosovo, Pristina, Kosovo.
⁸ Institute for Human Genetics, University Hospital Essen, Essen, Germany.
⁹ University Hospital of Nephrology, Faculty of Medicine, University "Ss Cyril and Methodius," Skopje, North Macedonia.
¹⁰ PHI SYNLAB Skopje Laboratories, Skopje, North Macedonia.
¹¹ Department of Pediatrics, Children's Hospital St. Elisabeth and St. Barbara, Halle (Saale), Germany.
¹² Department of Pediatrics, General Hospital, Celle, Germany.
¹³ Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.
¹⁴ Fundeni Clinical Institute, Pediatric Nephrology Department, Bucharest, Romania.
¹⁵ Department of Pediatrics II, University Children's Hospital, Philipps-University Marburg, Marburg, Germany.

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.

Keywords: Alport syndrome; COL4A5; X-inactivation; end-stage kidney disease; microscopic hematuria; proteinuria; urine-derived cells.

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.