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Ann Clin Transl Neurol. 2015 Jun;2(6):623-35. doi: 10.1002/acn3.198. Epub 2015 May 1.

De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.

Author information

1
Department of Neurology, University of California San Francisco, California, 94158.
2
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.
3
GeneDx Gaithersburg, Maryland.
4
Department of Pharmaceutical Chemistry, University of California San Francisco San Francisco, California.
5
Division of Human Genetics, Cincinnati Children's Hospital Medical Center Cincinnati, Ohio.
6
Division of Neurology, Cincinnati Children's Hospital Medical Center Cincinnati, Ohio.
7
Department of Pediatrics, Clinical Genetic Services, NYU School of Medicine New York, New York.
8
Division of Human Genetics, Cincinnati Children's Hospital Medical Center Cincinnati, Ohio ; Department of pediatrics, University of Cincinnati School of Medicine Cincinnati, Ohio.
9
Section of Medical Genetics, Department of Pediatrics, Duke University Durham, North Carolina.
10
Department of Neurology, University of California San Francisco, California, 94158 ; University of California San Diego, California.
11
Molecular Genetics Laboratory, and Metabolic-Neurogenetic Service, Wolfson Medical Center and Sackler Medical School, Tel Aviv University Tel Aviv, Israel.
12
Institute of Medical Genetics and Metabolic Neurogenetic Service, Wolfson Medical Center and Sackler Medical School, Tel Aviv University Tel Aviv, Israel.
13
Pediatric Neurology Unit and Metabolic Neurogenetic Service, Wolfson Medical Center, Holon and Sackler Medical School, Tel Aviv University Tel Aviv, Israel.
14
Department of Cellular and Molecular Pharmacology and the Howard Hughes Medical Institute, University of California San Francisco, California.
15
Department of Radiology and Biomedical Imaging, University of California San Francisco, California.

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.

INTERPRETATION:

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.

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