Favier R, Lavergne J M, Costa J M, Caron C, Mazurier C, Viémont M, Delpech M, Valleix S
Service d'Hématologie Biologique, Hôpital d'Enfants Armand Trousseau, Paris, France.
Blood. 2000 Dec 15;96(13):4373-5.
This report is of a 14-month-old girl affected with severe hemophilia A. Both her parents had normal values for factor VIII activity, and von Willebrand disease type 2N was excluded. Karyotype analysis demonstrated no obvious alteration, and BclI Southern blot did not reveal F8 gene inversions. Direct sequencing of F8 gene exons revealed a frameshift-stop mutation (Q565delC/ter566) in the heterozygous state in the proposita only. F8 gene polymorphism analysis indicated that the mutation must have occurred de novo in the paternal germline. Furthermore, analysis of the pattern of X chromosome methylation at the human androgen receptor gene locus demonstrated a skewed inactivation of the derived maternal X chromosome from the lymphocytes of the proband's DNA. Thus, the severe hemophilia A in the proposita results from a de novo F8 gene frameshift-stop mutation on the paternally derived X chromosome, associated with a nonrandom pattern of inactivation of the maternally derived X chromosome. (Blood. 2000;96:4373-4375)
本报告介绍了一名患有严重甲型血友病的14个月大女孩。她的父母因子VIII活性值均正常，且排除了2N型血管性血友病。核型分析未显示明显改变，BclI Southern印迹未揭示F8基因倒位。F8基因外显子的直接测序仅在先证者中发现了杂合状态的移码终止突变（Q565delC/ter566）。F8基因多态性分析表明，该突变一定是在父系生殖系中发生的新生突变。此外，对人类雄激素受体基因位点的X染色体甲基化模式分析表明，先证者DNA淋巴细胞中源自母亲的X染色体发生了偏态失活。因此，先证者的严重甲型血友病是由源自父系的X染色体上的新生F8基因移码终止突变引起的，与源自母亲的X染色体的非随机失活模式有关。（《血液》。2000年；96:4373 - 4375）
