X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction
X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction
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DOI：
10.1182/blood-2002-02-0387
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发表时间：
2002-09-15
期刊：
影响因子：
20.3
通讯作者：
Raskind, WH
中科院分区：
文献类型：
--
作者：
Yu, CN;Niakan, KK;Raskind, WH
转录因子 GATA-1 对于红细胞和巨核细胞的发育至关重要。它的 2 个锌指中的每一个对于正常功能都至关重要。 C 末端指对于 DNA 结合是必需的。 N指介导与FOG-1（GATA-1的辅助因子）的相互作用，并且还调节DNA结合亲和力，特别是在复杂或回文GATA位点。 N 指介导与 FOG-1 相互作用的残留物位于 N 指背对 DNA 的表面上。 DNA 残基的强序列保守性表明，另一个表面也可能发挥重要作用。我们在这里报告，人类 X 连锁血小板减少症伴地中海贫血的综合征是由 GATA-1 N 指中的错义突变 (Arg216Gln) 引起的。为了研究这种取代的功能后果，我们使用定点诱变来改变 GATA-1 中的相应残基。与野生型GATA-1相比，Arg216Gln GATA-1对单个GATA位点表现出相当的亲和力，但对回文位点的亲和力降低。 Arg216Gln GATA-1 与 FOG-1 的相互作用与野生型 GATA-1 类似。 Arg216Gln GATA-1 支持 GATA-1 红系细胞的红系成熟，尽管与野生型 GATA-1 相比效率较低。总之，这些发现表明，除了与辅因子 FOG-1 相互作用之外，面向 GATA-1 的 DNA 的 N 指残基还有助于 GATA-1 功能。这也是第一个由红系转录因子突变引起的人类β地中海贫血的例子。
Transcription factor GATA-1 is essential for the development of erythroid cells and megakaryocytes. Each of its 2 zinc fingers is critical for normal function. The C-terminal finger is necessary for DNA binding. The N finger mediates interaction with FOG-1, a cofactor for GATA-1, and also modulates DNA-binding affinity, notably at complex or palindromic GATA sites. Residues of the N finger-mediating interaction with FOG-1 lie on the surface of the N finger facing away from DNA. Strong sequence conservation of residues facing DNA suggests that this other surface may also have an important role. We report here that a syndrome of X-linked thrombocytopenia with thalassemia in humans is caused by a missense mutation (Arg216Gln) in the GATA-1 N finger. To investigate the functional consequences of this substitution, we used site-directed mutagenesis to alter the corresponding residue in GATA-1. Compared with wild-type GATA-1, Arg216Gln GATA-1 shows comparable affinity to single GATA sites but decreased affinity to palindromic sites. Arg216Gln GATA-1 interacts with FOG-1 similarly with wild-type GATA-1. Arg216Gln GATA-1 supports erythroid maturation of GATA-1 erythroid cells, albeit at reduced efficiency compared with wild-type GATA-1. Together, these findings suggest that residues of the N finger of GATA-1-facing DNA contribute to GATA-1 function apart from interaction with the cofactor FOG-1. This is also the first example of beta-thalassemia in humans caused by a mutation in an erythroid transcription factor.