title: De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.
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.
authors.affiliation: Biomedical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors.forename: Jae-Ran
authors.initials: JR
authors.lastname: Lee
authors.forename: Myriam
authors.initials: M
authors.lastname: Srour
authors.forename: Doyoun
authors.initials: D
authors.lastname: Kim
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: So-Hee
authors.initials: SH
authors.lastname: Lim
authors.forename: Catherine
authors.initials: C
authors.lastname: Brunel-Guitton
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Décarie
authors.forename: Elsa
authors.initials: E
authors.lastname: Rossignol
authors.forename: Grant A
authors.initials: GA
authors.lastname: Mitchell
authors.forename: Allison
authors.initials: A
authors.lastname: Schreiber
authors.forename: Rocio
authors.initials: R
authors.lastname: Moran
authors.forename: Keith
authors.initials: K
authors.lastname: Van Haren
authors.forename: Randal
authors.initials: R
authors.lastname: Richardson
authors.forename: Joost
authors.initials: J
authors.lastname: Nicolai
authors.forename: Karin M E J
authors.initials: KM
authors.lastname: Oberndorff
authors.forename: Justin D
authors.initials: JD
authors.lastname: Wagner
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.forename: Elisa
authors.initials: E
authors.lastname: Rahikkala
authors.forename: Nella
authors.initials: N
authors.lastname: Junna
authors.forename: Henna
authors.initials: H
authors.lastname: Tyynismaa
authors.forename: Inge
authors.initials: I
authors.lastname: Cuppen
authors.forename: Nienke E
authors.initials: NE
authors.lastname: Verbeek
authors.forename: Connie T R M
authors.initials: CT
authors.lastname: Stumpel
authors.forename: Michel A
authors.initials: MA
authors.lastname: Willemsen
authors.forename: Sonja A
authors.initials: SA
authors.lastname: de Munnik
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Eunjoon
authors.initials: E
authors.lastname: Kim
authors.forename: Erik-Jan
authors.initials: EJ
authors.lastname: Kamsteeg
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000235:genetics* / Q000473:pathology; D004827:Epilepsy / Q000235:genetics / Q000473:pathology; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000235:genetics / Q000473:pathology; D006801:Humans; D016547:Kinesins / Q000737:chemistry* / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D009422:Nervous System Diseases / Q000235:genetics* / Q000473:pathology; D020336:Paraparesis, Spastic / Q000235:genetics* / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000473:pathology; D017434:Protein Structure, Tertiary; D055815:Young Adult
chemical_list: C094065:KIF1A protein, human; D016547:Kinesins
keywords: KIF1A; axonal neuropathy; de novo mutations; intellectual disability; spastic paraparesis