Sickle cell disease caused by heterozygosity for Hb S and novel LCR deletion: Report of two patients

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 -珠蛋白基因的基因座控制区（LCR）位于胚胎ε -珠蛋白基因上游约6kb处，由5个DNA酶I超敏位点（HS1 - 5）组成。LCR在顺式调节下游的ε -、（G）γ -、（A）γ -、δ -和β -珠蛋白基因的表达中起关键作用[1]。已有文献描述患者中存在缺失LCR以及部分下游β -珠蛋白基因簇的情况[2]。这些个体呈现出（γδβ）⁰ -地中海贫血携带者表型。我们现在报道两名患有严重镰状细胞病的患者，他们是Hb S突变和新型LCR缺失的复合杂合子。在一个病例中，HS1 - 3缺失；在另一个病例中，HS1 - 5缺失。在这两种情况下，与LCR缺失处于顺式的β -样珠蛋白基因是完整的。从基因型上看，两名患者似乎都具有镰状细胞特征。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。这些LCR缺失的断点已确定。这些结果证实HS2和HS3主要负责赋予顺式连接的β -样珠蛋白基因红细胞特异性的高水平表达。此外，LCR缺失可能导致新生儿溶血病。