Division of Genetics and Cell Biology, San Raffaele Research Institute and Vita Salute University, Milano, Italy.
PLoS One. 2013 Jul 31;8(7):e69206. doi: 10.1371/journal.pone.0069206. Print 2013.
The red blood cell related traits are highly heritable but their genetics are poorly defined. Only 5-10% of the total observed variance is explained by the genetic loci found to date, suggesting that additional loci should be searched using approaches alternative to large meta analysis. GWAS (Genome Wide Association Study) for red blood cell traits in a founder population cohort from Northern Italy identified a new locus for mean corpuscular hemoglobin concentration (MCHC) in the TAF3 gene. The association was replicated in two cohorts (rs1887582, P = 4.25E-09). TAF3 encodes a transcription cofactor that participates in core promoter recognition complex, and is involved in zebrafish and mouse erythropoiesis. We show here that TAF3 is required for transcription of the SPTA1 gene, encoding alpha spectrin, one of the proteins that link the plasma membrane to the actin cytoskeleton. Mutations in SPTA1 are responsible for hereditary spherocytosis, a monogenic disorder of MCHC, as well as for the normal MCHC level. Based on our results, we propose that TAF3 is required for normal erythropoiesis in human and that it might have a role in controlling the ratio between hemoglobin (Hb) and cell volume and in the dynamics of RBC maturation in healthy individuals. Finally, TAF3 represents a potential candidate or a modifier gene for disorders of red cell membrane.
红细胞相关特征具有高度遗传性，但它们的遗传学尚未完全阐明。迄今为止，通过遗传位点发现的总观察方差只有 5-10%可以解释，这表明应该使用不同于大型荟萃分析的方法来搜索其他遗传位点。在意大利北部一个奠基人群体队列中进行的红细胞特征全基因组关联研究（GWAS）发现了 TAF3 基因中平均红细胞血红蛋白浓度（MCHC）的新位点。该关联在两个队列中得到了复制（rs1887582，P=4.25E-09）。TAF3 编码一种转录共因子，参与核心启动子识别复合物，并且在斑马鱼和小鼠的红细胞生成中发挥作用。我们在这里表明，TAF3 是编码α-血影蛋白的 SPTA1 基因转录所必需的，α-血影蛋白是将质膜与肌动蛋白细胞骨架连接的蛋白质之一。SPTA1 突变导致遗传性球形红细胞增多症，这是一种 MCHC 的单基因疾病，以及正常的 MCHC 水平。基于我们的结果，我们提出 TAF3 是人类正常红细胞生成所必需的，并且它可能在控制血红蛋白（Hb）与细胞体积的比例以及在健康个体中 RBC 成熟的动力学方面发挥作用。最后，TAF3 代表了红细胞膜疾病的潜在候选基因或修饰基因。
