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Günthner, R.* ; Knipping, L.* ; Jeruschke, S.* ; Satanoskij, R.* ; Lorenz-Depiereux, B. ; Hemmer, C.* ; Braunisch, M.C.* ; Riedhammer, K.M.* ; Ćomić, J.* ; Tönshoff, B.* ; Tasic, V.* ; Abazi-Emini, N.* ; Nushi-Stavileci, V.* ; Buiting, K.* ; Gjorgjievski, N.* ; Momirovska, A.* ; Patzer, L.* ; Kirschstein, M.* ; Gross, O.* ; Lungu, A.* ; Weber, S.* ; Renders, L.* ; Heemann, U.* ; Meitinger, T.* ; Büscher, A.K.* ; Hoefele, J.*

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

Front. Med. 9:953643 (2022)

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Alport Syndrome ; Col4a5 ; X-inactivation ; End-stage Kidney Disease ; Microscopic Hematuria ; Proteinuria ; Urine-derived Cells

ISSN (print) / ISBN 2296-858X

e-ISSN 2296-858X

Journal Frontiers in Medicine

Quellenangaben Volume: 9, Article Number: 953643

Publisher Frontiers

Publishing Place Lausanne

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Epidemiology II (EPI2)

Grants Technical University of Munich (TUM)
German Pediatric Nephrology Association