Severe hemophilia A in a Japanese female caused by an F8-intron 22 inversion associated with skewed X chromosome inactivation
Severe hemophilia A in a Japanese female caused by an F8-intron 22 inversion associated with skewed X chromosome inactivation
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DOI：
10.1007/s12185-010-0659-9
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发表时间：
2010-09-01
影响因子：
2.1
通讯作者：
Kojima, Tetsuhito
中科院分区：
文献类型：
--
作者：
Miyawaki, Yuhri;Suzuki, Atsuo;Kojima, Tetsuhito
血友病A是一种X连锁隐性出血性疾病，全球男性患病率约为1/5，000。血友病A是由凝血因子VIII（FVIII）缺乏或功能缺陷引起的，其临床严重程度与残留FVIII活性（FVIII：C）呈负相关。FVIII：C低于1、1-5和5-30%的患者分别被归类为重度、中度和轻度血友病A [1]。编码FVIII（F8）的基因位于X染色体长臂（Xq 28）的最远端区域，跨度为186 kb [2]。血友病A的分子基础已得到很好的表征，在血友病A患者的F8基因中发现了各种致病缺陷，如点突变、插入、缺失和其他遗传异常。其中，在包括日本人在内的约一半的重度血友病A病例中发现了在内含子22处破坏F8的大基因组倒位（F8-int 22倒位）[3-5]，并且在1-5%的病例中发现了内含子1处的倒位（F8-int 1倒位）[6，7]。血友病A影响男性，并通过杂合子女性传播，这些女性被称为携带者。它们通常是无症状的，因为它们具有失活的正常X染色体的体细胞比例近似等于具有失活的突变X染色体的比例[8]。然而，有几种潜在的遗传机制导致女性携带者（如血友病患者）中FVIII：C的表型表达非常低。因此，在极少数情况下，重度血友病A可发生在F8突变纯合子（例如，近亲）或复合杂合子的女性中[9，10]，通过X染色体异常，如X单体性（45 X，Turner综合征），以及由于杂合子女性携带者中的X失活偏斜[11，12]。在这项研究中，我们研究了F8缺陷的遗传机制，以阐明日本女性严重血友病A的分子发病机制。该研究得到了名古屋大学医学院伦理委员会的批准，在获得知情同意书后，通过如前所述的苯酚提取从外周血白细胞中分离所有参与者的基因组DNA样本[13]。患者为21岁女性，自2岁起出现出血症状，如易擦伤和关节肿胀。她被诊断为重度血友病A（FVIII：C\1%和FVIII：Ag\5%），并接受FVIII浓缩物作为替代治疗。然而，她的左肘关节出现血友病关节病。她的哥哥患有类似的出血症状，也被诊断为重度血友病A（FVIII：C\1%和FVIII：Ag\5%）。
Hemophilia A is an X-linked recessive bleeding disorder with a worldwide prevalence of approximately 1 in 5,000 males. Hemophilia A is caused by a deficiency or functional defect in coagulation factor VIII (FVIII), and its clinical severity is inversely related to residual FVIII activity (FVIII: C). Patients with less than 1, 1–5, and 5–30% FVIII: C are classified as having severe, moderate, and mild hemophilia A, respectively [1]. The gene encoding FVIII (F8) is located in the most distal region of the long arm of the X chromosome (Xq28) and spans 186 kb [2]. The molecular basis underlying hemophilia A is well characterized, and various causative defects, such as point mutations, insertions, deletions and other genetic abnormalities, have been found in the F8 gene of hemophilia A patients. Among them, a large genomic inversion disrupting F8 at intron 22 (F8-int22 inversion) is found in about half of severe hemophilia A cases including Japanese [3–5], and an inversion at intron 1 (F8-int1 inversion) is found in 1–5% of cases [6, 7]. Hemophilia A affects males, and is transmitted by heterozygous females who are denoted as carriers. They are usually asymptomatic, because their proportion of somatic cells with an inactivated normal X chromosome is approximately equal to the proportion with an inactivated mutated X chromosome [8]. However, there are several potential genetic mechanisms leading to the phenotypic expression of very low FVIII: C in female carriers as hemophiliacs. Thus, in rare cases, severe hemophilia A can occur in females homozygous (eg, consanguinity) or compound heterozygous for mutations in F8 [9, 10], through X chromosome abnormalities such as monosomy X (45 X, Turner syndrome), and due to skewed X inactivation in a heterozygous female carrier [11, 12]. In this study, we investigated the genetic mechanisms of F8 defects to elucidate the molecular pathogenesis responsible for severe hemophilia A in a Japanese female. The study was approved by the Ethics Committee of the Nagoya University School of Medicine, and genomic DNA samples from all participants were isolated from peripheral leukocytes by phenol extraction as described previously [13], after informed consents were obtained. The patient was a 21-year-old female and suffered from bleeding symptoms, such as easy bruising and joint swelling, since she was 2 years old. She was diagnosed as a severe hemophilia A (FVIII: C\1% and FVIII: Ag\5%), and received FVIII concentrates as replacement therapy. However, she had developed hemophiliac arthropathy in her left elbow joint. Her elder brother suffered from similar bleeding symptoms and had also been diagnosed as a severe hemophilia A (FVIII: C\1% and FVIII: Ag\5%).