Mutations in BICD2 Cause Dominant Congenital Spinal Muscular Atrophy and Hereditary Spastic Paraplegia
Mutations in BICD2 Cause Dominant Congenital Spinal Muscular Atrophy and Hereditary Spastic Paraplegia
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DOI：
10.1016/j.ajhg.2013.04.018
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发表时间：
2013-06-06
影响因子：
9.8
通讯作者：
Reilly, Mary M.
中科院分区：
文献类型：
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作者：
Oates, Emily C.;Rossor, Alexander M.;Reilly, Mary M.
显性先天性脊髓性肌萎缩症（DCSMA）是一种前角细胞发育障碍，表现出下肢优势，并与遗传性痉挛性截瘫（HSP），一种皮质脊髓运动神经元的下肢优势疾病的临床重叠。我们已经确定了四个突变的bicaudal D同系物2（果蝇）（BICD 2）在六个kinetics受DCSMA，DCSMA与上运动神经元功能，或HSP。BICD 2编码BICD 2，BICD 2是一种与动力蛋白-动力肌动蛋白运动复合体相互作用的关键衔接蛋白，其促进对运动神经元发育和维持至关重要的细胞货物的运输。我们证明，突变导致氨基酸取代在两个结合区域的BICD 2增加其结合亲和力的细胞质动力蛋白-动力肌动蛋白复合物，这可能会导致BICD 2-动力蛋白-动力肌动蛋白介导的贩运的扰动，并损害神经突生长。这些发现提供了对静态和缓慢进展的临床特征以及表征BICD 2相关疾病的运动神经元病理学的机制的深入了解，并强调了动力蛋白-动力蛋白转运途径在下运动神经元和上运动神经元的发育和存活中的重要性。
Dominant congenital spinal muscular atrophy (DCSMA) is a disorder of developing anterior horn cells and shows lower-limb predominance and clinical overlap with hereditary spastic paraplegia (HSP), a lower-limb-predominant disorder of corticospinal motor neurons. We have identified four mutations in bicaudal D homolog 2 (Drosophila) (BICD2) in six kindreds affected by DCSMA, DCSMA with upper motor neuron features, or HSP. BICD2 encodes BICD2, a key adaptor protein that interacts with the dynein-dynactin motor complex, which facilitates trafficking of cellular cargos that are critical to motor neuron development and maintenance. We demonstrate that mutations resulting in amino acid substitutions in two binding regions of BICD2 increase its binding affinity for the cytoplasmic dynein-dynactin complex, which might result in the perturbation of BICD2-dynein-dynactin-mediated trafficking, and impair neurite outgrowth. These findings provide insight into the mechanism underlying both the static and the slowly progressive clinical features and the motor neuron pathology that characterize BICD2-associated diseases, and underscore the importance of the dynein-dynactin transport pathway in the development and survival of both lower and upper motor neurons.