Department of Pediatrics, Hangzhou Children's Hospital, Hangzhou, Zhejiang, China.
Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang, China.
Medicine (Baltimore). 2023 May 5;102(18):e33665. doi: 10.1097/MD.0000000000033665.
Hemophilia A (HA) is an X-linked recessive bleeding disorder, which shows factor VIII (FVIII) deficiency caused by genetic variant in F8 gene.
Males with F8 variants are affected, whereas female carriers with a wide range of FVIII levels are usually asymptomatic, it is possible that different X-chromosome inactivation (XCI) may effect the FVIII activity.
We identified a novel variant F8: c.6193T > G in a Chinese HA proband, it was inherited from the mother and grandmother with different FVIII levels.
We performed Androgen receptor gene (AR) assays and RT-PCR.
AR assays revealed that the X chromosome with the F8 variant was severely skewed inactivated in the grandmother with higher FVIII levels, but not in the mother with lower FVIII levels. Further, RT-PCR of mRNA confirmed that only the wild allele of F8 was expressed in the grandmother, with lower expression in the wild allele of the mother.
Our findings suggest that F8: c.6193T > G could be the cause of HA and that XCI affected the FVIII plasma levels in female carriers.
血友病 A (HA) 是一种 X 连锁隐性出血性疾病，由 F8 基因中的遗传变异导致因子 VIII (FVIII) 缺乏。
男性受 F8 变异影响，而具有广泛 FVIII 水平的女性携带者通常无症状，不同的 X 染色体失活 (XCI) 可能会影响 FVIII 活性。
我们在一名中国 HA 先证者中鉴定出一种新型 F8 变异：c.6193T > G，它来自于具有不同 FVIII 水平的母亲和祖母。
我们进行了雄激素受体基因 (AR) 检测和 RT-PCR。
AR 检测显示，具有 F8 变异的 X 染色体在 FVIII 水平较高的祖母中严重失活偏倚，但在 FVIII 水平较低的母亲中则没有。此外，mRNA 的 RT-PCR 证实，只有野生型 F8 等位基因在祖母中表达，而母亲的野生型等位基因表达水平较低。
我们的研究结果表明，F8: c.6193T > G 可能是 HA 的病因，XCI 影响女性携带者的 FVIII 血浆水平。
