Arbini A A, Bodkin D, Lopaciuk S, Bauer K A
Department of Medicine, Brockton-West Roxbury Department of Veterans Affairs Medical Center, MA 02132.
Blood. 1994 Oct 1;84(7):2214-20.
We analyzed the mutations in patients from 10 Polish kindreds with a bleeding diathesis due to factor VII deficiency. Patients from eight families had plasma levels of factor VII coagulant activity (VII:C) and factor VII antigen (VII:Ag) that were less than 4% of normal. The coding sequence of the factor VII gene was amplified from genomic DNA by polymerase chain reaction (PCR). Sequencing demonstrated a C to T transition at position 10798 resulting in Ala294Val, a G to A transition at 10976 resulting in Arg353Gln, and a single bp deletion at 11125 to 11128 causing a frameshift mutation in the triplet encoding amino acid 404. Homozygosity for the three sequence alterations was confirmed with the restriction enzymes AvaII and MspI and allele specific PCR, respectively. A homozygous patient from a ninth family with levels of VII:C and VII:Ag of 4% and 17%, respectively, had Ala294Val and the frameshift mutation, but not Arg353Gln. Investigation of a homozygous patient from a tenth kindred with VII:C and VII:Ag of 11% and 47%, respectively, demonstrated Ala294Val and Arg353Gln, but not the frameshift mutation. Based on the above data, we conclude that the frameshift mutation in the codon for amino acid 404 is associated with marked reductions in VII:C, Arg353Gln can decrease plasma levels of factor VII in the presence of other mutations in the factor VII gene, and Ala294Val results in a dysfunctional factor VII molecule.
我们分析了来自10个患有因因子VII缺乏导致出血素质的波兰家族的患者的突变情况。8个家族的患者血浆中因子VII凝血活性（VII:C）和因子VII抗原（VII:Ag）水平低于正常水平的4%。通过聚合酶链反应（PCR）从基因组DNA中扩增因子VII基因的编码序列。测序显示在第10798位发生C到T的转变，导致丙氨酸294变为缬氨酸；在第10976位发生G到A的转变，导致精氨酸353变为谷氨酰胺；在11125至11128位有一个单碱基缺失，导致编码第404位氨基酸的三联体发生移码突变。分别用限制性内切酶AvaII和MspI以及等位基因特异性PCR证实了这三种序列改变的纯合性。来自第九个家族的一名纯合患者，其VII:C和VII:Ag水平分别为4%和17%，具有丙氨酸294变为缬氨酸和移码突变，但没有精氨酸353变为谷氨酰胺。对来自第十个家族的一名纯合患者进行研究，其VII:C和VII:Ag水平分别为11%和47%，结果显示有丙氨酸294变为缬氨酸和精氨酸353变为谷氨酰胺，但没有移码突变。基于上述数据，我们得出结论：第404位氨基酸密码子中的移码突变与VII:C的显著降低有关，在因子VII基因存在其他突变的情况下，精氨酸353变为谷氨酰胺会降低因子VII的血浆水平，而丙氨酸294变为缬氨酸会导致因子VII分子功能失调。
