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首页> 外文OA文献 >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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Compound heterozygosity of novel missense mutations in the gamma-glutamyl-carboxylase gene causes hereditary combined vitamin K–dependent coagulation factor deficiency

机译：γ-谷氨酰羧化酶基因中新的错义突变的复合杂合性导致遗传性联合维生素K依赖性凝血因子缺乏症

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摘要

Hereditary combined vitamin K–dependent (VKD) coagulation factor deficiency is an autosomal recessive bleeding disorder associated with defects in either the γ-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 wild-type carboxylase, and their compound heterozygosity can therefore account for functional VKD factor deficiency. The implications for carboxylase mechanism are discussed.
机译：遗传性综合维生素K依赖（VKD）凝血因子缺乏症是一种常染色体隐性出血性疾病，与γ-羧化酶（使VKD蛋白羧化以使其具有活性）或维生素K环氧还原酶（VKORC1）缺陷相关。减少了羧化所需的维生素K辅助因子。这种缺陷很少见，我们报告了第四例病例，该病例是由羧化酶基因突变引起的，该突变是在突尼斯女孩中发现的，该女孩在止血VKD因子中功能受损，而维生素K给药未能恢复该功能。对蛋白质组进行的序列分析未发现VKORC1基因中的任何突变，但显着地揭示了羧化酶基因中的3个杂合突变，这些突变导致了Asp31Asn，Trp157Arg和Thr591Lys的取代。这些突变以前均未报道。家庭分析表明，Asp31Asn和Thr591Lys是由母体传播的，而Trp157Arg是由父亲传播的，对100个健康个体的基因组筛选排除了频繁的多态性。突变分析表明Asp31Asn羧化酶具有野生型活性。相反，Trp157Arg和Thr591Lys的活性分别是野生型羧化酶的8％和0％，因此它们的复合杂合性可以解释功能性VKD因子缺乏的原因。讨论了羧化酶机理的意义。

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