Koenig Sara C, Becirevic Esmira, Hellberg Miriam S C, Li Michael Y, So Jason C C, Hankins Jane S, Ware Russell E, McMahon Lillian, Steinberg Martin H, Luo Hong-Yuan, Chui David H K
Am J Hematol. 2009 Sep;84(9):603-6. doi: 10.1002/ajh.21480.
The b-globin gene LCR is located approximately 6 kb upstream of the embryonic epsilon-globin gene, and is made up of five DNase I hypersensitive sites (HSs), HS 1-5. LCR plays a pivotal role in regulating the expression of downstream epsilon-, (G)gamma-, (A)gamma-, delta-, and beta-globin genes in cis [1]. Deletions removing the LCR and parts of the downstream beta-globin gene cluster in patients have been described [2]. These individuals present with a (gammadeltabeta)0-thalassemia carrier phenotype. We now report two patients with severe sickle cell disease who were compound heterozygous for Hb S mutation and novel LCR deletion. In one case, HS 1-3 were deleted; in the other, HS 1-5 were deleted. In both cases, the b-like globin genes in cis to the LCR deletions were intact. Genotypically, both patients appeared to have sickle cell trait. Coinherited with either LCR deletion, these individuals presented as sickle cell disease patients. The breakpoints of these LCR deletions were defined. These results affirm that HS 2 and 3 are primarily responsible for conferring erythroid specific high-level expression of cis-linked beta-like globin genes. Furthermore, LCR deletions might cause hemolytic disease of newborns.
β-珠蛋白基因座控制区（LCR）位于胚胎期ε-珠蛋白基因上游约6 kb处，由5个DNA酶I超敏位点（HSs），即HS 1 - 5组成。LCR在顺式调控下游的ε-、（G）γ-、（A）γ-、δ-和β-珠蛋白基因的表达中起关键作用[1]。已有报道称患者存在LCR及部分下游β-珠蛋白基因簇缺失的情况[2]。这些个体表现为（γδβ）0-地中海贫血携带者表型。我们现报告2例患有严重镰状细胞病的患者，他们为Hb S突变和新型LCR缺失的复合杂合子。1例缺失HS 1 - 3；另1例缺失HS 1 - 5。在这两例中，与LCR缺失处于顺式位置的类β-珠蛋白基因均完整。从基因型上看，这两名患者似乎都有镰状细胞性状。与任何一种LCR缺失共同遗传时，这些个体表现为镰状细胞病患者。确定了这些LCR缺失的断点。这些结果证实，HS 2和HS 3主要负责赋予顺式连接的类β-珠蛋白基因红系特异性的高水平表达。此外，LCR缺失可能导致新生儿溶血病。
