Compound heterozygosity of novel missense mutations in the gamma-glutamyl-carboxylase gene causes hereditary combined vitamin K-dependent coagulation factor deficiency
Compound heterozygosity of novel missense mutations in the gamma-glutamyl-carboxylase gene causes hereditary combined vitamin K-dependent coagulation factor deficiency
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DOI：
10.1182/blood-2005-12-010660
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发表时间：
2006-09-15
期刊：
影响因子：
20.3
通讯作者：
Rosa, Jean-Philippe
中科院分区：
文献类型：
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作者：
Darghouth, Dhouha;Hallgren, Kevin W.;Rosa, Jean-Philippe
遗传性联合维生素K依赖性（VKD）凝血因子缺乏症是一种常染色体隐性遗传性出血性疾病，与γ-羧化酶或维生素K环氧化物还原酶（VKORC 1）缺陷相关，γ-羧化酶可使VKD蛋白羧化，使其具有活性，而维生素K环氧化物还原酶可提供羧化所需的还原型维生素K辅因子。这种缺陷是罕见的，我们报告了第四例羧化酶基因突变，在突尼斯女孩谁表现出功能受损的止血VKD因素，没有恢复维生素K管理。先证者的序列分析未发现VKORC 1基因中的任何突变，但值得注意的是，发现羧化酶基因中有3个杂合突变，导致Asp 31 Asn、Trp 157 Arg和Thr 591 Lys取代。这些突变以前都没有报道过。家系分析显示Asp 31 Asn和Thr 591 Lys为共等位基因，且为母系遗传，Trp 157 Arg为父系遗传，对100例健康个体的基因组筛查排除了常见的多态性。突变分析表明野生型活性的Asp 31 Asn羧化酶。相反，Trp 157 Arg和Thr 591 Lys活性分别为野生型羧化酶的8%和0%，因此它们的复合杂合性可以解释功能性VKD因子缺乏。羧化酶机制的影响进行了讨论。
Hereditary combined vitamin K-dependent (VKD) coagulation factor deficiency is an autosomal recessive bleeding disorder associated with defects in either the gamma-carboxylase, which carboxylates VKD proteins to render them active, or the vitamin K epoxide reductase (VKORC1), which supplies the reduced vitamin K cofactor required for carboxylation. Such deficiencies are rare, and we report the fourth case resulting from mutations in the carboxylase gene, identified in a Tunisian girl who exhibited impaired function in hemostatic VKD factors that was not restored by vitamin K administration. Sequence analysis of the proposita did not identify any mutations in the VKORC1 gene but, remarkably, revealed 3 heterozygous mutations in the carboxylase gene that caused the substitutions Asp31Asn, Trp157Arg, and Thr591Lys. None of these mutations have previously been reported. Family analysis showed that Asp31Asn and Thr591Lys were coallelic and maternally transmitted while Trp157Arg was transmitted by the father, and a genomic screen of 100 healthy individuals ruled out frequent polymorphisms. Mutational analysis indicated wild-type activity for the Asp31Asn carboxylase. In contrast, the respective Trp157Arg and Thr591Lys activities were 8% and 0% that of wildtype carboxylase, and their compound heterozygosity can therefore account for functional VKD factor deficiency. The implications for carboxylase mechanism are discussed.