Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.
Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.
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DOI：
10.1056/nejmoa1512234
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发表时间：
2016-03-17
期刊：
影响因子：
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通讯作者：
Rosenzweig SD
中科院分区：
文献类型：
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作者：
Kuehn HS;Boisson B;Cunningham-Rundles C;Reichenbach J;Stray-Pedersen A;Gelfand EW;Maffucci P;Pierce KR;Abbott JK;Voelkerding KV;South ST;Augustine NH;Bush JS;Dolen WK;Wray BB;Itan Y;Cobat A;Sorte HS;Ganesan S;Prader S;Martins TB;Lawrence MG;Orange JS;Calvo KR;Niemela JE;Casanova JL;Fleisher TA;Hill HR;Kumánovics A;Conley ME;Rosenzweig SD
常见变异型免疫缺陷（CVID）的特征是在无诱发因素的情况下发生迟发性低丙种球蛋白血症。大多数病例的遗传原因尚不清楚，只有不到10%的患者有家族病史。大多数患者有正常数量的B细胞，但缺乏浆细胞。我们使用全外显子组测序和基于阵列的比较基因组杂交来评估CVID和低B细胞数量的患者子集。使用电泳迁移率变动分析（EMSA）和共聚焦显微镜分析突变蛋白的DNA结合。采用流式细胞术分析外周血淋巴细胞和骨髓穿刺液。6个不同的杂合突变IKZF 1，基因编码的转录因子IKAROS，被确定在29人从6个家庭。在两个家庭中，突变是一个从头事件的先证者。所有的突变，四个氨基酸取代，基因内缺失，和4.7-Mb多基因缺失涉及IKAROS的DNA结合结构域。携带错义突变的蛋白质未能结合靶DNA序列的EMSA和共聚焦显微镜，但是，他们没有抑制野生型IKAROS的结合。对家族成员的研究显示B细胞和血清免疫球蛋白进行性丢失。两名患者的骨髓穿刺液中早期B细胞前体细胞明显减少，但存在浆细胞。29例患者中有2例发生急性淋巴细胞白血病。转录因子IKAROS的杂合突变导致常染色体显性形式的CVID，其与B细胞数量的显著减少相关。（由美国国立卫生研究院和其他机构资助。
Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.)