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

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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; Myriam Srour; Doyoun Kim; Fadi. F. Hamdan; So-Hee Lim; Catherine Brunel-Guitton; Jean-Claude Decarie; Elsa Rossignol; Grant A. Mitchell; Allison Schreiber; Rocio Moran; Keith Van Haren; Randal Richardson; Joost Nicolai; Karin M.E.J Oberndorff; Justin D. Wagner; Kym M. Boycott; Elisa Rahikkala; Nella Junna; Henna Tyynismaa; Inge Cuppen; Nienke E. Verbeek; Connie T.R.M. Stumpel; Michel A. Willemsen; Sonja A. de Munnik; Guy A. Rouleau; Eunjoon Kim; Erik-Jan Kamsteeg; Tjitske Kleefstra; Jacques L. Michaud
Publication Date
2015-01
Journal
HUMAN MUTATION, v.36, no.1, pp.69 - 78
Publisher
WILEY-BLACKWELL
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.
URI
https://pr.ibs.re.kr/handle/8788114/825
ISSN
1059-7794
Appears in Collections:
Center for Synaptic Brain Dysfunctions(시냅스 뇌질환 연구단) > Journal Papers (저널논문)
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