New mutations in C1GALT1C1 in individuals with Tn positive phenotype
New mutations in C1GALT1C1 in individuals with Tn positive phenotype
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DOI：
10.1111/j.1365-2141.2008.07215.x
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发表时间：
2008-08-01
影响因子：
6.5
通讯作者：
Anstee, David J.
中科院分区：
文献类型：
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作者：
Crew, Vanja Karamatic;Singleton, Belinda K.;Anstee, David J.
Tn多聚凝集由C1 GALT 1C 1的失活突变引起，C1 GALT 1C 1是一种X携带基因，编码T合酶（β 1，3-半乳糖基转移酶）功能所需的核心1 β 3-半乳糖基转移酶特异性分子伴侣（cosmc），T合酶是O-聚糖正确生物合成所必需的糖基转移酶。本研究发现新的失活突变（Glu 152 Lys，Ser 193 Pro和Met 1 Ile）的编码序列的C1 GALT 1C 1在三个Tn阳性个体和一个完全缺乏C1 GALT 1C 1 cDNA表达观察到在额外的Tn阳性个体。此外，ST 6 GALNAC 1的表达，其编码（α-N-乙酰-神经氨酰-2，3-β-半乳糖基-1，3）-N-乙酰半乳糖胺α-2，6-唾液酸转移酶1并产生唾液酸-Tn抗原，在正常和Tn阳性人成红细胞中以相当的水平存在。野生型和Tn阳性C1 GALT 1C 1 cDNA在Jurkat细胞系中的表达研究证实，在Tn中观察到的氨基酸取代是失活的。对培养的正常和Tn阳性成红细胞的转录组进行分析，发现基因表达存在许多差异。通过定量实时聚合酶链反应证实了脂肪酸结合蛋白5（FABP 5）和丛蛋白D1（PLXND 1）转录水平的降低以及水通道蛋白3（AQP 3）水平的增加。这些数据表明，由T-合酶缺乏引起的O-聚糖结构的改变伴随着红系细胞中多种基因表达的改变。
Tn polyagglutination results from inactivating mutations in C1GALT1C1, an X-borne gene encoding a core 1 beta 3-galactosyltransferase-specific molecular chaperone (cosmc) required for the functioning of T-synthase (beta 1,3-galactosyltransferase), a glycosyltransferase essential for the correct biosynthesis of O-glycans. This study found novel inactivating mutations (Glu152Lys, Ser193Pro and Met1Ile) in the coding sequence of C1GALT1C1 in three Tn positive individuals and a complete lack of C1GALT1C1 cDNA expression was observed in an additional Tn positive individual. In addition, expression of ST6GALNAC1, which encodes (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1, 3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 and gives rise to sialyl-Tn antigen, was present at comparable levels in normal and Tn-positive human erythroblasts. Expression studies of wild-type and Tn positive C1GALT1C1 cDNA in the Jurkat cell line confirmed that the amino acid substitutions observed in Tn are inactivating. Analysis of the transcriptome of cultured normal and Tn positive erythroblasts revealed numerous differences in gene expression. Reduced transcript levels for fatty acid binding protein 5 (FABP5) and plexin D1 (PLXND1), and increased levels for aquaporin 3 (AQP3) were confirmed by quantitative real-time polymerase chain reaction. These data show that alteration of O-glycan structures resulting from T-synthase deficiency is accompanied by altered expression of a wide variety of genes in erythroid cells.