Journal
HUMAN MUTATION
Volume 36, Issue 1, Pages 69-78Publisher
WILEY
DOI: 10.1002/humu.22709
Keywords
KIF1A; intellectual disability; spastic paraparesis; axonal neuropathy; de novo mutations
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Funding
- Fondation Jean-Louis Levesque
- Netherlands Organization for Health Research and Development (ZonMw) [907-00-365]
- Basic Science Research Program through the National Research Foundation of Korea (NRF) [2012R1A2A2A02014520]
- Postgenomic Research Program [NRF-2014M3C9A2064619]
- KRIBB research initiative program [KGM1141413]
- Institute for Basic Sciences [IBS-R002-D1]
- Genome Canada
- Canadian Institutes of Health Research
- Ontario Genomics Institute
- Ontario Research Fund
- Genome Quebec
- Children's Hospital of Eastern Ontario Foundation
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KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.
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