Abstract
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.
Highlights
KIF1A is a motor protein that is expressed exclusively in the brain and transports cargoes from the cell body to peripheral ends of neurites[1,2]
We identified a novel p.T258M mutation in KIF1A affecting mother and three children with spastic paraplegia that is inherited in a type of autosomal dominant manner
The inheritance of complicated hereditary spastic paraplegia (HSP) with intellectual disability has not been reported as far, and our p.T258M KIF1A mutation is the first case of autosomal dominant inheritance in familial complicated HSP (Table 2)
Summary
KIF1A is a motor protein that is expressed exclusively in the brain and transports cargoes from the cell body to peripheral ends of neurites[1,2]. Various heterozygous de novo missense mutations on the KIF1A motor domain have been identified in patients who display intellectual disability along with atrophy and spastic paraplegia[14,15,16,17]. We report the first case of familial complicated HSP with a KIF1A mutation transmitted in autosomal dominant inheritance. This p.T258M mutation is located in the conserved sequences of the motor domain, and was identified from four patients in a family of HSP along with mild intellectual disability, language delay, optic nerve atrophy, thinning of corpus callosum, periventricular white matter lesion, microcephaly, and epilepsy. This novel heterozygous p.T258M mutation with autosomal dominant inheritance is meaningful in that it expands the phenotypic spectrum of KIF1A variants to include intellectual disability and spastic paraplegia
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