PDF(Pubmed)
Abstract：
Mutations within immunoglobulin mu DNA binding protein (IGHMBP2), an RNA-DNA helicase, result in SMA with respiratory distress type I (SMARD1) and Charcot Marie Tooth type 2S (CMT2S). The underlying biochemical mechanism of IGHMBP2 is unknown as well as the functional significance of IGHMBP2 mutations in disease severity. Here we report the biochemical mechanisms of IGHMBP2 disease-causing mutations D565N and H924Y, and their potential impact on therapeutic strategies. The IGHMBP2-D565N mutation has been identified in SMARD1 patients, while the IGHMBP2-H924Y mutation has been identified in CMT2S patients. For the first time, we demonstrate a correlation between the altered IGHMBP2 biochemical activity associated with the D565N and H924Y mutations and disease severity and pathology in patients and our Ighmbp2 mouse models. We show that IGHMBP2 mutations that alter the association with activator of basal transcription (ABT1) impact the ATPase and helicase activities of IGHMBP2 and the association with the 47S pre-rRNA 5\' external transcribed spacer. We demonstrate that the D565N mutation impairs IGHMBP2 ATPase and helicase activities consistent with disease pathology. The H924Y mutation alters IGHMBP2 activity to a lesser extent while maintaining association with ABT1. In the context of the compound heterozygous patient, we demonstrate that the total biochemical activity associated with IGHMBP2-D565N and IGHMBP2-H924Y proteins is improved over IGHMBP2-D565N alone. Importantly, we demonstrate that the efficacy of therapeutic applications may vary based on the underlying IGHMBP2 mutations and the relative biochemical activity of the mutant IGHMBP2 protein.
摘要：
免疫球蛋白muDNA结合蛋白（IGHMBP2）内的突变，RNA-DNA解旋酶,导致SMA伴呼吸窘迫I型（SMARD1）和CharcotMarieTooth2S型（CMT2S）。IGHMBP2的潜在生化机制以及IGHMBP2突变在疾病严重程度中的功能意义尚不清楚。在这里，我们报道了IGHMBP2致病突变D565N和H924Y的生化机制，以及它们对治疗策略的潜在影响。已在SMARD1患者中鉴定出IGHMBP2-D565N突变，而IGHMBP2-H924Y突变已在CMT2S患者中被鉴定。第一次,我们证明了与D565N和H924Y突变相关的IGHMBP2生化活性改变与患者和我们的Ighmbp2小鼠模型的疾病严重程度和病理之间的相关性.我们表明，IGHMBP2突变改变了与基础转录激活剂（ABT1）的关联，影响了IGHMBP2的ATPase和解旋酶活性，以及与47Spre-rRNA5'外部转录间隔区的关联。我们证明D565N突变损害IGHMBP2ATP酶和解旋酶活性与疾病病理一致。H924Y突变在较小程度上改变IGHMBP2活性,同时维持与ABT1的关联。在复合杂合患者的情况下，我们证明与IGHMBP2-D565N和IGHMBP2-H924Y蛋白相关的总生化活性比单独的IGHMBP2-D565N提高。重要的是,我们证明,治疗应用的功效可能因潜在的IGHMBP2突变和突变IGHMBP2蛋白的相对生化活性而异.
