title: De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.
abstract: OBJECTIVE
  To determine the cause and course of a novel syndrome with progressive encephalopathy and brain atrophy in children.
  
  
  METHODS
  Clinical whole-exome sequencing was performed for global developmental delay and intellectual disability; some patients also had spastic paraparesis and evidence of clinical regression. Six patients were identified with de novo missense mutations in the kinesin gene KIF1A. The predicted functional disruption of these mutations was assessed in silico to compare the calculated conformational flexibility and estimated efficiency of ATP binding to kinesin motor domains of wild-type (WT) versus mutant alleles. Additionally, an in vitro microtubule gliding assay was performed to assess the effects of de novo dominant, inherited recessive, and polymorphic variants on KIF1A motor function.
  
  
  RESULTS
  All six subjects had severe developmental delay, hypotonia, and varying degrees of hyperreflexia and spastic paraparesis. Microcephaly, cortical visual impairment, optic neuropathy, peripheral neuropathy, ataxia, epilepsy, and movement disorders were also observed. All six patients had a degenerative neurologic course with progressive cerebral and cerebellar atrophy seen on sequential magnetic resonance imaging scans. Computational modeling of mutant protein structures when compared to WT kinesin showed substantial differences in conformational flexibility and ATP-binding efficiency. The de novo KIF1A mutants were nonmotile in the microtubule gliding assay.
  
  
  CONCLUSIONS
  De novo mutations in KIF1A cause a degenerative neurologic syndrome with brain atrophy. Computational and in vitro assays differentiate the severity of dominant de novo heterozygous versus inherited recessive KIF1A mutations. The profound effect de novo mutations have on axonal transport is likely related to the cause of progressive neurologic impairment in these patients.
authors.affiliation: Department of Neurology, University of California San Francisco, California, 94158.
authors.forename: Sahar
authors.initials: S
authors.lastname: Esmaeeli Nieh
authors.affiliation: Department of Neurology, University of California San Francisco, California, 94158.
authors.forename: Maura R Z
authors.initials: MR
authors.lastname: Madou
authors.affiliation: Department of Cellular and Molecular Pharmacology and the Howard Hughes Medical Institute, University of California San Francisco, California ; Cardiovascular Biology and Diseases, Institute of Stem Cell Biology and Regenerative Medicine, NCBS-TIFR Bangalore, India.
authors.forename: Minhajuddin
authors.initials: M
authors.lastname: Sirajuddin
authors.affiliation: Department of Neurology, University of California San Francisco, California, 94158.
authors.forename: Brieana
authors.initials: B
authors.lastname: Fregeau
authors.affiliation: GeneDx Gaithersburg, Maryland.
authors.forename: Dianalee
authors.initials: D
authors.lastname: McKnight
authors.affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco San Francisco, California.
authors.forename: Katrina
authors.initials: K
authors.lastname: Lexa
authors.affiliation: Department of Neurology, University of California San Francisco, California, 94158.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Strober
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center Cincinnati, Ohio.
authors.forename: Christine
authors.initials: C
authors.lastname: Spaeth
authors.affiliation: Division of Neurology, Cincinnati Children's Hospital Medical Center Cincinnati, Ohio.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Hallinan
authors.affiliation: GeneDx Gaithersburg, Maryland.
authors.forename: Nizar
authors.initials: N
authors.lastname: Smaoui
authors.affiliation: Department of Pediatrics, Clinical Genetic Services, NYU School of Medicine New York, New York.
authors.forename: John G
authors.initials: JG
authors.lastname: Pappas
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center Cincinnati, Ohio ; Department of pediatrics, University of Cincinnati School of Medicine Cincinnati, Ohio.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Burrow
authors.affiliation: Section of Medical Genetics, Department of Pediatrics, Duke University Durham, North Carolina.
authors.forename: Marie T
authors.initials: MT
authors.lastname: McDonald
authors.affiliation: Department of Neurology, University of California San Francisco, California, 94158 ; University of California San Diego, California.
authors.forename: Mariam
authors.initials: M
authors.lastname: Latibashvili
authors.affiliation: Molecular Genetics Laboratory, and Metabolic-Neurogenetic Service, Wolfson Medical Center and Sackler Medical School, Tel Aviv University Tel Aviv, Israel.
authors.forename: Esther
authors.initials: E
authors.lastname: Leshinsky-Silver
authors.affiliation: Institute of Medical Genetics and Metabolic Neurogenetic Service, Wolfson Medical Center and Sackler Medical School, Tel Aviv University Tel Aviv, Israel.
authors.forename: Dorit
authors.initials: D
authors.lastname: Lev
authors.affiliation: Pediatric Neurology Unit and Metabolic Neurogenetic Service, Wolfson Medical Center, Holon and Sackler Medical School, Tel Aviv University Tel Aviv, Israel.
authors.forename: Luba
authors.initials: L
authors.lastname: Blumkin
authors.affiliation: Department of Cellular and Molecular Pharmacology and the Howard Hughes Medical Institute, University of California San Francisco, California.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Vale
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, California.
authors.forename: Anthony James
authors.initials: AJ
authors.lastname: Barkovich
authors.affiliation: Department of Neurology, University of California San Francisco, California, 94158.
authors.forename: Elliott H
authors.initials: EH
authors.lastname: Sherr