Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation
Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation
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DOI：
10.1182/blood.v98.1.85
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发表时间：
2001-07-01
期刊：
影响因子：
20.3
通讯作者：
Van Geet, C
中科院分区：
文献类型：
--
作者：
Freson, K;Devriendt, K;Van Geet, C
X连锁基因GATA1中描述了一种新的突变，导致4代家族出现巨血小板减少症和轻度红细胞生成障碍特征，但没有明显贫血。观察到的表型的分子基础是在转录因子 GATA1 的氨基末端锌指环的严格保守的密码子 218 (D218G) 中甘氨酸取代了天冬氨酸，锌指相互作用研究表明，这种突变导致 GATA1 与其必需辅因子 FOG1 的亲和力微弱丧失，而 DP18G-GATA1 与 DNA 的直接结合是正常的。已经研究了这种突变对患者血小板的表型影响，半定量 RNA 分析（针对 p-肌动蛋白信使 RNA 进行标准化）显示 GATA1 靶基因 GPIb beta 和 GPIX 的转录极低，而且非直接 GATA1 调节的 Gs alpha 基因的表达也显着降低，表明巨核细胞成熟不完全。相反，GPIIIa 表达接近正常，与其在巨核细胞分化过程中的早期出现一致。对患者血小板的流式细胞术分析证实存在尺寸分布异常和 GPIb 复合物水平降低但 GPIIIa 表达正常的血小板群。它还显示存在非常不成熟的血小板，缺乏几乎所有研究的膜糖蛋白（GPIb α、GPIb β、GPIIIa、GPIX 和 GPV）。患者的血小板表现出微弱的瑞斯托菌素诱导的凝集，与受干扰的 GPIb 复合物相容。因此，患者血小板的电子显微镜显示巨大的血小板具有由光滑内质网和异常膜复合物组成的细胞质簇。总之，GATA1 突变可导致孤立性 X 连锁巨血小板减少症，但不伴有贫血。 (C) 2001 年，美国血液学会。
A new mutation is described in the X-linked gene GATA1, resulting in macrothrombocytopenia and mild dyserythropoietic features but no marked anemia in a 4-generation family. The molecular basis for the observed phenotype is a substitution of glycine for aspartate in the strictly conserved codon 218 (D218G) of the amino-terminal zinc finger loop of the transcription factor GATA1, Zinc finger interaction studies demonstrated that this mutation results in a weak loss of affinity of GATA1 for its essential cofactor FOG1, whereas direct DP18G-GATA1 binding to DNA was normal. The phenotypic effects of this mutation in the patients' platelets have been studied, Semiquantitative RNA analysis, normalized for p-actin messenger RNA, showed extremely low transcription of the GATA1 target genes GPIb beta and GPIX but also a significantly lower expression of the nondirectly GATA1-regulated Gs alpha gene, suggestive of incomplete megakaryocyte maturation. In contrast, GPIIIa expression was close to normal in agreement with its early appearance during megakaryocyte differentiation. Flow cytometric analysis of patient platelets confirmed the existence of a platelet population with abnormal size distribution and reduced GPIb complex levels but with normal GPIIIa expression. It also showed the presence of very immature platelets lacking almost all membrane glycoproteins studied (GPIb alpha, GPIb beta, GPIIIa, GPIX, and GPV), Patients' platelets showed weak ristocetin-induced agglutination, compatible with the disturbed GPIb complex. Accordingly, electron microscopy of the patients' platelets revealed giant platelets with cytoplasmic clusters consisting of smooth endoplasmic reticulum and abnormal membrane complexes. In conclusion, GATA1 mutations can lead to isolated X-linked macrothrombocytopenia without anemia. (C) 2001 by The American Society of Hematology.