A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10)
A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10)
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DOI：
10.1086/344210
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发表时间：
2002-11-01
影响因子：
9.8
通讯作者：
Marchuk, DA
中科院分区：
文献类型：
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作者：
Reid, E;Kloos, M;Marchuk, DA
我们在一个遗传性痉挛性截瘫家族中发现了神经元驱动蛋白重链基因KIF 5A运动域的错义突变。突变发生在SPG10基因座最初被鉴定的家族中，突变发生在不变的天冬酰胺残基处，当在orthoglycardinesin重链马达蛋白中突变时，该天冬酰胺残基阻止微管结合对马达ATP酶的刺激。不同物种中驱动蛋白同源物的突变导致类似遗传性痉挛性截瘫的表型。传统的驱动蛋白马达驱动膜性细胞器和其他大分子货物从神经元细胞体到轴突远端的细胞内运动。这一发现表明，SPG10和可能的其他形式的遗传性痉挛性截瘫的潜在病理可能涉及神经元顺行（或逆行）轴浆流的扰动，导致轴突变性，特别是在中枢神经系统的最长轴突。
We have identified a missense mutation in the motor domain of the neuronal kinesin heavy chain gene KIF5A, in a family with hereditary spastic paraplegia. The mutation occurs in the family in which the SPG10 locus was originally identified, at an invariant asparagine residue that, when mutated in orthologous kinesin heavy chain motor proteins, prevents stimulation of the motor ATPase by microtubule-binding. Mutation of kinesin orthologues in various species leads to phenotypes resembling hereditary spastic paraplegia. The conventional kinesin motor powers intracellular movement of membranous organelles and other macromolecular cargo from the neuronal cell body to the distal tip of the axon. This finding suggests that the underlying pathology of SPG10 and possibly of other forms of hereditary spastic paraplegia may involve perturbation of neuronal anterograde (or retrograde) axoplasmic flow, leading to axonal degeneration, especially in the longest axons of the central nervous system.