KIF1A is a brain-specific anterograde motor protein that transports cargoes towards the plus-ends of microtubules. Many variants of the KIF1A gene have been associated with neurodegenerative diseases and developmental delay. Homozygous mutations of KIF1A have been identified in a recessive subtype of hereditary spastic paraplegia (HSP), SPG30. In addition, KIF1A mutations have been found in pure HSP with autosomal dominant inheritance. Here we report the first case of familial complicated HSP with a KIF1A mutation transmitted in autosomal dominant inheritance. A heterozygous p.T258M mutation in KIF1A was found in a Korean family through targeted exome sequencing. They displayed phenotypes of mild intellectual disability with language delay, epilepsy, optic nerve atrophy, thinning of corpus callosum, periventricular white matter lesion, and microcephaly. A structural modeling revealed that the p.T258M mutation disrupted the binding of KIF1A motor domain to microtubules and its movement along microtubules. Assays of peripheral accumulation and proximal distribution of KIF1A motor indicated that the KIF1A motor domain with p.T258M mutation has reduced motor activity and exerts a dominant negative effect on wild-type KIF1A. These results suggest that the p.T258M mutation suppresses KIF1A motor activity and induces complicated HSP accompanying intellectual disability transmitted in autosomal dominant inheritance.

中文翻译：

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由于KIF1A SPG30基因的显性负突变，导致复杂的遗传性痉挛性截瘫的常染色体显性遗传。

KIF1A是大脑特异的顺行运动蛋白，可将货物运送至微管的正端。KIF1A基因的许多变体与神经退行性疾病和发育延迟有关。已在遗传性痉挛性截瘫（HSP）的隐性亚型SPG30中鉴定出KIF1A的纯合突变。此外，已经在具有常染色体显性遗传的纯HSP中发现了KIF1A突变。在这里，我们报告的第一例家族性HSP伴有在常染色体显性遗传中传递的KIF1A突变。通过靶向外显子组测序在韩国家庭中发现了KIF1A中的杂合p.T258M突变。他们表现出轻度智力障碍的表型，包括语言延迟，癫痫，视神经萎缩，call体变薄，脑室周围白质病变，和小头畸形。结构模型表明，p.T258M突变破坏了KIF1A运动域与微管的结合及其沿微管的运动。对KIF1A马达的周围累积和近端分布的测定表明，具有p.T258M突变的KIF1A马达结构域具有降低的马达活性，并且对野生型KIF1A产生显着的负作用。这些结果表明p.T258M突变抑制KIF1A运动活动，并诱导伴随常染色体显性遗传的智力残疾的复杂HSP。对KIF1A马达的周围累积和近端分布的测定表明，具有p.T258M突变的KIF1A马达结构域具有降低的马达活性，并且对野生型KIF1A产生显着的负作用。这些结果表明p.T258M突变抑制KIF1A运动活动，并诱导伴随常染色体显性遗传的智力残疾的复杂HSP。KIF1A运动的周边积累和近端分布的分析表明，具有p.T258M突变的KIF1A运动域降低了运动活性，并对野生型KIF1A发挥了主要的负面作用。这些结果表明p.T258M突变抑制KIF1A运动活动，并诱导伴随常染色体显性遗传的智力残疾的复杂HSP。