De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy
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- De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy
- 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
- HUMAN MUTATION, v.36, no.1, pp.69 - 78
- 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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