当前位置: X-MOL 学术Eur. J. Hum. Genet. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
X Chromosome inactivation: a modifier of factor VIII and IX plasma levels and bleeding phenotype in Haemophilia carriers
European Journal of Human Genetics ( IF 5.2 ) Pub Date : 2020-10-20 , DOI: 10.1038/s41431-020-00742-4
Isabella Garagiola 1 , Mimosa Mortarino 1 , Simona Maria Siboni 1 , Marco Boscarino 1 , Maria Elisa Mancuso 1 , Marina Biganzoli 1 , Elena Santagostino 1 , Flora Peyvandi 1, 2
Affiliation  

Haemophilia A and B are X-linked hemorrhagic disorders caused by gene variants in the F8 and F9 genes. Due to recessive inheritance, males are affected, while female carriers are usually asymptomatic with a wide range of factor VIII (FVIII) or IX (FIX) levels. Bleeding tendency in female carriers is extremely variable and may be associated with low clotting factor levels. This could be explained by F8 or F9 genetic variations, numerical or structural X chromosomal anomalies, or epigenetic variations such as irregular X chromosome inactivation (XCI). The aim of the study was to determine whether low FVIII or FIX coagulant activity in haemophilia carriers could be related to XCI and bleeding symptoms. HUMARA assay was performed on 73 symptomatic carriers with low clotting activity ≤50 IU/dL. Bleeding Assessment Tool (BAT) from the International Society on Thrombosis and Haemostasis (ISTH) was used to describe symptoms in the cohort of carriers. In 97% of haemophilia carriers, a specific gene variant in heterozygous state was found, which alone could not justify their low FVIII or FIX levels (≤50 IU/dL). A statistical association between XCI pattern and FVIII and FIX levels was observed. Moreover, female carriers with low coagulant activity (≤20 IU/dL) and high degree of XCI ( ≥ 80:20) had a higher ISTH-BAT score than the carriers with the opposite conditions (>20 IU/dL and <80:20). In our cohort of haemophilia carriers, XCI was significantly skewed, which may contribute to the low expression of clotting factor levels and bleeding symptoms.



中文翻译:

X 染色体失活:血友病携带者中凝血因子 VIII 和 IX 血浆水平和出血表型的调节剂

血友病 A 和 B 是由F8F9基因中的基因变异引起的 X 连锁出血性疾病。由于隐性遗传,男性受到影响,而女性携带者通常无症状,具有广泛的因子 VIII (FVIII) 或 IX (FIX) 水平。女性携带者的出血倾向变化很大,可能与凝血因子水平低有关。这可以用F8F9来解释遗传变异、数值或结构 X 染色体异常,或表观遗传变异,如不规则 X 染色体失活 (XCI)。该研究的目的是确定血友病携带者的低 FVIII 或 FIX 凝血活性是否与 XCI 和出血症状有关。对 73 名具有低凝血活性≤50 IU/dL 的有症状携带者进行了 HUMRA 检测。国际血栓和止血协会 (ISTH) 的出血评估工具 (BAT) 用于描述携带者队列中的症状。在 97% 的血友病携带者中,发现了杂合状态的特定基因变体,仅凭这一点并不能证明他们的 FVIII 或 FIX 水平低(≤50 IU/dL)。观察到 XCI 模式与 FVIII 和 FIX 水平之间的统计关联。而且,具有低凝血活性 (≤20 IU/dL) 和高度 XCI (≥ 80:20) 的女性携带者的 ISTH-BAT 评分高于具有相反条件的携带者 (>20 IU/dL 和 <80:20) . 在我们的血友病携带者队列中,XCI 显着偏斜,这可能导致凝血因子水平和出血症状的低表达。

更新日期:2020-10-20
down
wechat
bug