Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age.
Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age.
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DOI：
10.3389/fmed.2022.953643
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发表时间：
2022
影响因子：
3.9
通讯作者：
Hoefele, Julia
中科院分区：
文献类型：
--
作者：
Gunthner, Roman;Knipping, Lea;Jeruschke, Stefanie;Satanoskij, Robin;Lorenz-Depiereux, Bettina;Hemmer, Clara;Braunisch, Matthias C.;Riedhammer, Korbinian M.;Comic, Jasmina;Tonshoff, 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;Buscher, Anja K.;Hoefele, Julia
关键词：
由COL4A5半合子致病变异引起的x连锁Alport综合征（AS）主要影响男性。杂合状态的女性表现出多种表型谱，从显微镜下的血尿到终末期肾脏疾病（ESKD）和肾外表现。在其他x连锁疾病中，偏x失活导致一条x染色体优先沉默，因此可以决定女性的表型。我们的目的是显示血液和尿源性肾细胞中x失活与携带COL4A5杂合致病变异的女性临床表型之间的相关性。本研究共纳入56例携带COL4A5杂合致病变异的女性，平均年龄为31.6±18.3 SD年。总共94%的患者有血尿，62%的患者有蛋白尿，但只有7%的患者eGFR下降。使用人类雄激素受体测定法检测了所有56个人的血细胞、其中27个人的尿源细胞和所有健康对照者的x失活。x -失活与首次表现的年龄、蛋白尿或eGFR无关，无论是在血液中还是在尿液中。x -失活程度显示与年龄适度相关，特别是在患者队列的尿源性细胞中（rho = 0.403, p = 0.037）。x失活等位基因的测定揭示了x失活向COL4A5变异等位基因的转移。这是第一个检测来自女性AS患者尿源性细胞x失活的研究。在患有AS的女性个体中，没有观察到表型与x失活之间的相关性，怀疑其他遗传修饰因子塑造了表型。尿源性细胞中x失活与年龄的关联表明，在患有AS的女性个体中，一种逃逸机制使携带等位基因的COL4A5变异体失活。
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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