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De Novo Mutations in the Motor Domain of KIF1A Cause Cognitive Impairment, Spastic Paraparesis, Axonal Neuropathy, and Cerebellar Atrophy
Author(s) -
Lee JaeRan,
Srour Myriam,
Kim Doyoun,
Hamdan Fadi. F.,
Lim SoHee,
BrunelGuitton Catherine,
Décarie JeanClaude,
Rossignol Elsa,
Mitchell Grant A.,
Schreiber Allison,
Moran Rocio,
Haren Keith,
Richardson Randal,
Nicolai Joost,
Oberndorff Karin M.E.J.,
Wagner Justin D.,
Boycott Kym M.,
Rahikkala Elisa,
Junella,
Tyynismaa Henna,
Cuppen Inge,
Verbeek Nienke E.,
Stumpel Connie T.R.M.,
Willemsen Michel A.,
Munnik Sonja A.,
Rouleau Guy A.,
Kim Eunjoon,
Kamsteeg ErikJan,
Kleefstra Tjitske,
Michaud Jacques L.
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22709
Subject(s) - missense mutation , biology , mutation , genetics , atrophy , hereditary spastic paraplegia , phenotype , gene
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.