Molecular genetics of hereditary prothrombin deficiency in Indian patients:: identification of a novel Ala362→Thr (Prothrombin Vellore 1) mutation
Molecular genetics of hereditary prothrombin deficiency in Indian patients:: identification of a novel Ala362→Thr (Prothrombin Vellore 1) mutation
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DOI：
10.1111/j.1538-7836.2005.01402.x
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发表时间：
2005-07-01
影响因子：
10.4
通讯作者：
Srivastava, A
中科院分区：
文献类型：
--
作者：
Jayandharan, G;Viswabandya, A;Srivastava, A
凝血酶原缺乏症是一种罕见的常染色体隐性遗传病，由凝血酶原基因的多种突变引起。我们研究了四名无关的印度患者的这种疾病的分子基础。诊断是基于延长凝血酶原（PT）和活化部分凝血活素时间和低因子11凝血活性（FII: C）测量使用PT为基础的分析。FII: C水平介于4.7%至17.5%之间。在所有四名患者中都发现了突变。鉴定出五种不同的致病突变，包括四种（80%）错义和一种帧内缺失（20%）。其中之一是一种新的，Ala362 -> Thr氨基酸改变影响α -凝血酶的‘B’链。该突变以复合杂合状态存在，先前报道的ArgI - b> Gin错义改变影响前肽切割位点。Ala362 -> Thr发生在一个密码子上，在所有24种不同的凝血酶原或其相关丝氨酸蛋白酶中都是进化保守的。该突变的分子模型被发现引起该区域周围的构象变化，涉及催化三联体残基His363和密码子364的半胱氨酸残基。患者FII: C水平为17.5%。另外三个先前报道的突变也在纯合状态下被检测到：Kringle-2区域的Arg271 - b> Cys， a-凝血酶a链上的Glu309 -> Lys和a-凝血酶a链上的3bp的框内缺失（AAG）导致Del Lys301/302。这是印度患者凝血酶原缺乏的分子基础的第一篇报道，我们建议将Ala362 -> Thr突变命名为“凝血酶原Vellore 1”。
Prothrombin deficiency is a rare (1:200 000) autosomal recessive disorder caused by diverse mutations in prothrombin gene. We have studied the molecular basis of this disorder in four unrelated Indian patients. The diagnosis was based on prolonged prothrombin (PT) and activated partial thromboplastin times and low factor 11 coagulant activity (FII: C) measured using a PT based assay. FII: C levels ranged between 4.7% and 17.5%. Mutations were identified in all the four patients. Five different causative mutations including four (80%) missense and an in-frame deletion (20%) were identified. One of them was a novel, Ala362 -> Thr aminoacid change affecting 'B' chain of alpha-thrombin. This mutation was present in a compound heterozygous state with a previously reported ArgI -> Gin missense change affecting pro-peptide cleavage site. Ala362 -> Thr occurred at a codon, evolutionarily conserved in all the 24 different prothrombins or its related serine proteases studied. Molecular modeling of this mutation was found to cause a conformational change around the region involving a catalytic triad residue His363 and a cysteine residue at codon 364. The FII: C level in this patient was 17.5%. Three other previously reported mutations were also detected in the homozygous state: Arg271 -> Cys in Kringle-2 region, a Glu309 -> Lys in 'A' chain of a-thrombin and an in-frame deletion of 3 bp (AAG) leading to Del Lys301/302 in 'A' chain of alpha-thrombin. This is the first report of the molecular basis of prothrombin deficiency in Indian patients and we suggest the eponym'Prothrombin Vellore 1' for Ala362 -> Thr mutation.