Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome
Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome
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DOI：
10.1038/10385
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发表时间：
1999-07-01
期刊：
影响因子：
30.8
通讯作者：
Gelb, BD
中科院分区：
文献类型：
--
作者：
Diaz, GA;Banikazemi, M;Gelb, BD
硫胺反应性巨幼细胞贫血综合征（TRMA; MIM 249270）是一种常染色体隐性遗传病，其特征包括巨幼细胞贫血、轻度血小板减少和白细胞减少、感音神经性耳聋和糖尿病（1-3）。用药理学剂量的硫胺素治疗可改善巨幼细胞性贫血和糖尿病。在TRMA患者的红细胞和培养的皮肤成纤维细胞中发现了硫胺素的质膜运输缺陷（4-6）。通过连锁分析，TRMA基因定位于1q23.2-q23.3(7)。在这里，我们报道了一个新基因SLC19A2的克隆，该基因从高通量基因组序列中鉴定出与SLC19A1同源，编码减少叶酸载体1（参考文献8-10）。我们通过筛选人类胎儿大脑cDNA文库克隆了整个编码区。SLC19A2编码一个蛋白（497 aa），预计有12个跨膜结构域。我们在四个伊朗TRMA家族中发现了2个外显子移码突变，1个1 bp的插入和2 bp的缺失。SLC19A2的序列同源性、预测结构及其在TRMA中的作用表明，其基因产物是一种硫胺素载体，首次在复杂真核生物中被鉴定出来。
Thiamine-responsive megaloblastic anaemia syndrome (TRMA; MIM 249270) is an autosomal recessive disorder with features that include megaloblastic anaemia, mild thrombocytopenia and leucopenia, sensorineural deafness and diabetes mellitus(1-3). Treatment with pharmacologic doses of thiamine ameliorates the megaloblastic anaemia and diabetes mellitus. A defect in the plasma membrane transport of thiamine has been demonstrated in erythrocytes and cultured skin fibroblasts from TRMA patients(4-6). The gene causing TRMA was assigned to 1q23.2-q23.3 by linkage analysis(7). Here we report the cloning of a new gene, SLC19A2, identified from high-throughput genomic sequences due to homology with SLC19A1, encoding reduced folate carrier 1 (refs 8-10). We cloned the entire coding region by screening a human fetal brain cDNA library. SLC19A2 encodes a protein (of 497 aa) predicted to have 12 transmembrane domains. We identified 2 frameshift mutations in exon 2, a 1-bp insertion and a 2-bp deletion, among four Iranian families with TRMA. The sequence homology and predicted structure of SLC19A2, as well as its role in TRMA, suggest that its gene product is a thiamine carrier, the first to be identified in complex eukaryotes.