Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K.
Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K.
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DOI：
10.1084/jem.20112533
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发表时间：
2012-03-12
期刊：
影响因子：
--
通讯作者：
Murray PJ
中科院分区：
文献类型：
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作者：
Conley ME;Dobbs AK;Quintana AM;Bosompem A;Wang YD;Coustan-Smith E;Smith AM;Perez EE;Murray PJ
1例PIK3R1纯合子过早终止密码子的患者表现出B细胞发育的早期发育障碍，但对其他器官系统的影响很小。采用外显子全序列测序法对原因不明的B细胞缺陷患者的致病基因进行分析。在1例B细胞缺失的结肠炎患者中发现PIK3R1基因第6外显子的纯合子提前终止密码子。突变导致P85α缺失，但PI3K的p50α和p55α调节亚基正常表达。患者骨髓抽吸物中有0.1%的CD19+B细胞，−B细胞前体细胞比例正常。这种发育障碍比B细胞受体信号通路缺陷的患者或具有类似P85α缺陷的工程化小鼠更早出现。患者T细胞数量和功能均正常。然而，Western印迹显示患者T细胞、中性粒细胞和树突状细胞中p110δ显著降低，而p85α缺失。患者生长发育正常，空腹血糖和胰岛素正常。P85α缺乏的小鼠有胰岛素过敏、血小板功能缺陷和肥大细胞发育异常。相反，患者中缺乏P85α会导致B细胞发育的早期和严重缺陷，但在其他器官系统的发现很少。
A patient with a homozygous premature stop codon in PIK3R1 showed an early developmental block in B cell development but minimal effects in other organ systems. Whole exome sequencing was used to determine the causative gene in patients with B cell defects of unknown etiology. A homozygous premature stop codon in exon 6 of PIK3R1 was identified in a young woman with colitis and absent B cells. The mutation results in the absence of p85α but normal expression of the p50α and p55α regulatory subunits of PI3K. Bone marrow aspirates from the patient showed <0.1% CD19+ B cells with normal percentages of TdT+VpreB+CD19− B cell precursors. This developmental block is earlier than that seen in patients with defects in the B cell receptor signaling pathway or in a strain of engineered mice with a similar defect in p85α. The number and function of the patient’s T cells were normal. However, Western blot showed markedly decreased p110δ, as well as absent p85α, in patient T cells, neutrophils, and dendritic cells. The patient had normal growth and development and normal fasting glucose and insulin. Mice with p85α deficiency have insulin hypersensitivity, defective platelet function, and abnormal mast cell development. In contrast, the absence of p85α in the patient results in an early and severe defect in B cell development but minimal findings in other organ systems.