A Point Mutation in Glycoprotein IX Coding Sequence (Cys73(TGT) to Tyr(TAT)) Causes Impaired Surface Expression of GPIb/IX/V Complex in Two Families with Bernard-Souiier Syndrome
A Point Mutation in Glycoprotein IX Coding Sequence (Cys73(TGT) to Tyr(TAT)) Causes Impaired Surface Expression of GPIb/IX/V Complex in Two Families with Bernard-Souiier Syndrome
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糖蛋白 IX 编码序列中的点突变（Cys73(TGT) 至 Tyr(TAT)）导致两个 Bernard-Souiier 综合征家系的 GPIb/IX/V 复合物表面表达受损
DOI：
10.1055/s-0038-1650678
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发表时间：
1996
影响因子：
6.7
通讯作者：
Masayuki Sano
中科院分区：
文献类型：
--
作者：
M. Noda;K. Fujimura;T. Takafuta;T. Shimomura;T. Fujii;S. Katsutani;T. Fujimoto;A. Kuramoto;T. Yamazaki;T. Mochizuki;M. Matsuzaki;Masayuki Sano
Bernard-Soulier综合征（BSS）是一种罕见的遗传性出血性疾病，由糖蛋白（GP） Ib/IX/V复合物的异常表达或功能引起，GP是血小板中von Wille-brand因子的主要受体。我们研究了四个BSS患者在两个不相关的家庭中发现相同的和新的突变。流式细胞术分析显示GPIX完全缺失，但GPIbα和GPV在这些患者中可检测到残留量。采用聚合酶链反应（PCR）从患者基因组DNA中扩增GPIbα、GPIbβ、GPV和GPIX的编码区。在所有四个病例中，我们在GPIX编码区发现了一个点突变，该突变将半胱氨酸73 （TGT）的密码子改变为酪氨酸（TAT）的密码子。此外，我们通过瞬时表达研究证实，突变导致GPIX失去足够的表面表达。由于半胱氨酸可能对GPIX的二级结构很重要，因此GPIX基因的突变会导致GPIX蛋白的构象发生剧烈变化，导致表面表达减少。我们得出结论，这种新的GPIX基因点突变是导致这些家庭BSS的原因
Summary Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder which is caused by abnormal expression or function of the glycoprotein (GP) Ib/IX/V complex, a platelet major receptor for von Wille-brand factor. We studied four BSS patients in two unrelated families in which the same and novel mutation was found. Flow cytometric analysis showed that GPIX was completely absent but residual amounts of GPIbα and GPV were detectable in these patients. We analyzed all coding regions of GPIbα, GPIbβ, GPV and GPIX which were amplified from the patients’ genomic DNA by the polymerase chain reaction (PCR). In all four cases, we identified a point mutation in the GPIX coding region that changes the codon for cysteine 73 (TGT) to a codon for tyrosine (TAT). Furthermore, we confirmed by a transient expression study that the mutation caused the loss of adequate surface expression of GPIX. Since cysteine might be important for the secondary structure, this mutation of GPIX gene would lead to a dramatic conformational change of GPIX protein, resulting in the reduced surface expression. We concluded that this novel point mutation of the GPIX gene was responsible for BSS in these families