De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy

Cited 72 time in scopus
Metadata Downloads
Title
De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy
Author(s)
Jae-Ran Lee; S Srour; D Kim; F F Hamdan; So Hee Lim; C Brunel-Guitton; J C Decarie; E Rossignol; G A Mitchell; A Schreiber; R Moran; K V Haren; R Richardson; J Nicolai; K M E J Oberndorff; J D Wagner; K M Boycott; E Rahikkala; N Junna; H Tyynismaa; I Cuppen; N E Verbeek; C T R M Stumpel; M A Willemsen; S A Munnik; G A Rouleau; E Kim; E J Kamsteeg; T Kleefstra; J L Michaud
Bibliographic Citation
Human Mutation, vol. 36, no. 1, pp. 69-78
Publication Year
2015
Abstract
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.
Keyword
Axonal neuropathyDe novo mutationsIntellectual disabilityKIF1ASpastic paraparesis
ISSN
1059-7794
Publisher
Wiley
DOI
http://dx.doi.org/10.1002/humu.22709
Type
Article
Appears in Collections:
Division of Biomedical Research > Rare Disease Research Center > 1. Journal Articles
Files in This Item:
  • There are no files associated with this item.


Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.