Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, 53127 Bonn, Germany.
Haematologica. 2010 Jun;95(6):956-62. doi: 10.3324/haematol.2009.017210. Epub 2010 Feb 23.
Severe hereditary coagulation factor XIII deficiency is a rare homozygous bleeding disorder affecting one person in every two million individuals. In contrast, heterozygous factor XIII deficiency is more common, but usually not associated with severe hemorrhage such as intracranial bleeding or hemarthrosis. In most cases, the disease is caused by F13A gene mutations. Causative mutations associated with the F13B gene are rarer.
We analyzed ten index patients and three relatives for factor XIII activity using a photometric assay and sequenced their F13A and F13B genes. Additionally, structural analysis of the wild-type protein structure from a previously reported X-ray crystallographic model identified potential structural and functional effects of the missense mutations.
All individuals except one were heterozygous for factor XIIIA mutations (average factor XIII activity 51%), while the remaining homozygous individual was found to have severe factor XIII deficiency (<5% of normal factor XIII activity). Eight of the 12 heterozygous patients exhibited a bleeding tendency upon provocation.
The identified missense (Pro289Arg, Arg611His, Asp668Gly) and nonsense (Gly390X, Trp664X) mutations are causative for factor XIII deficiency. A Gly592Ser variant identified in three unrelated index patients, as well as in 200 healthy controls (minor allele frequency 0.005), and two further Tyr167Cys and Arg540Gln variants, represent possible candidates for rare F13A gene polymorphisms since they apparently do not have a significant influence on the structure of the factor XIIIA protein. Future in vitro expression studies of the factor XIII mutations are required to confirm their pathological mechanisms.
严重遗传性凝血因子 XIII 缺乏症是一种罕见的纯合子出血性疾病，每两百万人中就有一人患病。相比之下，杂合子因子 XIII 缺乏症更为常见，但通常不会导致颅内出血或关节积血等严重出血。在大多数情况下，该病由 F13A 基因突变引起。由 F13B 基因突变引起的致病突变则较为罕见。
我们使用光密度测定法分析了 10 名指数患者和 3 名亲属的因子 XIII 活性，并对他们的 F13A 和 F13B 基因进行了测序。此外，我们还从之前报道的 X 射线晶体结构模型中鉴定出野生型蛋白结构的结构分析，以确定错义突变的潜在结构和功能影响。
除 1 人外，所有个体均为因子 XIIIa 突变的杂合子（平均因子 XIII 活性为 51%），而其余的纯合子个体则发现存在严重的因子 XIII 缺乏症（正常因子 XIII 活性的<5%）。12 名杂合子患者中有 8 名在受到刺激时表现出出血倾向。
鉴定出的错义突变（Pro289Arg、Arg611His、Asp668Gly）和无义突变（Gly390X、Trp664X）是导致因子 XIII 缺乏症的原因。在 3 名无关联的指数患者以及 200 名健康对照者中（次要等位基因频率为 0.005）发现 Gly592Ser 变体，以及另外两个 Tyr167Cys 和 Arg540Gln 变体，它们可能是罕见的 F13A 基因突变的候选者，因为它们显然不会对因子 XIIIa 蛋白的结构产生重大影响。未来需要进行因子 XIII 突变的体外表达研究以确认其病理机制。
