Millar D S, Kemball-Cook G, McVey J H, Tuddenham E G, Mumford A D, Attock G B, Reverter J C, Lanir N, Parapia L A, Reynaud J, Meili E, von Felton A, Martinowitz U, Prangnell D R, Krawczak M, Cooper D N
Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, UK.
Hum Genet. 2000 Oct;107(4):327-42. doi: 10.1007/s004390000373.
Factor VII (FVII) deficiency is a rare haemorrhagic condition, normally inherited as an autosomal recessive trait, in which clinical presentation is highly variable and correlates poorly with laboratory phenotype. The FVII (F7) gene was sequenced in 48 unrelated individuals with FVII deficiency, yielding a total of 23 novel lesions including 15 missense mutations, 2 micro-deletions, 5 splice junction mutations and a single base-pair substitution in the 5' untranslated region. Family studies were performed in order to distinguish the contributions of individual mutant F7 alleles to the clinical and laboratory phenotypes. Specific missense mutations were evaluated by molecular modelling in the context of the FVIIa-tissue factor crystal structure. Single base-pair substitutions in splice sites and the 5' untranslated region were studied by in vitro splicing assay and luciferase reporter gene assay, respectively. All probands were also typed for four previously reported F7 polymorphisms. In the majority of cases of FVII deficiency studied here, consideration of both mutational and polymorphism data permitted the derivation of plausible explanations for the FVII activity and antigen levels measured in the laboratory. Inter-familial variation in FVII activity and the antigen levels of heterozygous relatives of probands was found to be significantly higher than intra-familial variation, consistent with the view that the nature of the F7 gene lesion(s) segregating in a given family is a prime determinant of laboratory phenotype. Although no relationship could be discerned between laboratory phenotype and polymorphism genotype, the frequencies of the A2 and M2 polymorphic alleles were significantly higher in the FVII-deficient individuals tested than in controls. This suggests that the presence of these alleles may have served to increase the likelihood of pathological F7 gene lesions coming to clinical attention.
凝血因子 VII（FVII）缺乏症是一种罕见的出血性疾病，通常作为常染色体隐性性状遗传，其临床表现高度可变，与实验室表型的相关性较差。对48名无亲缘关系的FVII缺乏症个体的FVII（F7）基因进行了测序，共发现23个新的病变，包括15个错义突变、2个微缺失、5个剪接位点突变以及5'非翻译区的一个单碱基对替换。进行了家系研究，以区分各个突变F7等位基因对临床和实验室表型的影响。在FVIIa-组织因子晶体结构的背景下，通过分子建模评估特定的错义突变。分别通过体外剪接试验和荧光素酶报告基因试验研究剪接位点和5'非翻译区的单碱基对替换。所有先证者还对四个先前报道的F7多态性进行了分型。在这里研究的大多数FVII缺乏症病例中，综合考虑突变和多态性数据，可以对实验室检测到的FVII活性和抗原水平得出合理的解释。发现先证者杂合亲属的FVII活性和抗原水平的家系间差异显著高于家系内差异，这与以下观点一致，即在给定家族中分离的F7基因病变的性质是实验室表型的主要决定因素。虽然在实验室表型和多态性基因型之间未发现相关性，但在检测的FVII缺乏症个体中，A2和M2多态性等位基因的频率显著高于对照组。这表明这些等位基因的存在可能增加了病理性F7基因病变引起临床关注的可能性。
