title: Autosomal recessive mutations in nuclear transport factor KPNA7 are associated with infantile spasms and cerebellar malformation.
abstract: Nuclear import receptors of the KPNA family recognize the nuclear localization signal in proteins and together with importin-β mediate translocation into the nucleus. Accordingly, KPNA family members have a highly conserved architecture with domains that contact the nuclear localization signal and bind to importin-β. Here, we describe autosomal recessive mutations in KPNA7 found by whole exome sequencing in a sibling pair with severe developmental disability, infantile spasms, subsequent intractable epilepsy consistent with Lennox-Gastaut syndrome, partial agenesis of the corpus callosum, and cerebellar vermis hypoplasia. The mutations mapped to exon 7 in KPNA7 result in two amino-acid substitutions, Pro339Ala and Glu344Gln. On the basis of the crystal structure of the paralog KPNA2 bound to a bipartite nuclear localization signal from the retinoblastoma protein, the amino-acid substitutions in the affected subjects were predicted to occur within the seventh armadillo repeat that forms one of the two nuclear localization signal-binding sites in KPNA family members. Glu344 is conserved in all seven KPNA proteins, and we found that the Glu354Gln mutation in KPNA2 is sufficient to reduce binding to the retinoblastoma nuclear localization signal to approximately one-half that of wild-type protein. Our data show that compound heterozygous mutations in KPNA7 are associated with a human neurodevelopmental disease, and provide the first example of a human disease associated with mutation of a nuclear transport receptor.
authors.affiliation: 1] Departments of Neurology, Pediatrics and Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA [2] Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Alex R
authors.initials: AR
authors.lastname: Paciorkowski
authors.affiliation: Departments of Neurology and Pediatrics, Pediatric Epilepsy Center, Washington University, St Louis, MO, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Weisenberg
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Kelley
authors.affiliation: Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Spencer
authors.affiliation: Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Tuttle
authors.affiliation: Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Dalia
authors.initials: D
authors.lastname: Ghoneim
authors.affiliation: Departments of Neurology and Pediatrics, Pediatric Epilepsy Center, Washington University, St Louis, MO, USA.
authors.forename: Liu Lin
authors.initials: LL
authors.lastname: Thio
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Christian
authors.affiliation: 1] Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA [2] Departments of Pediatrics and Neurology, University of Washington, Seattle, WA, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: 1] Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA [2] Departments of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
authors.forename: Bryce M
authors.initials: BM
authors.lastname: Paschal
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001921:Brain / Q000473:pathology; D002531:Cerebellum / Q000002:abnormalities*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D059472:Exome; D019066:Facies; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D013036:Spasms, Infantile / Q000175:diagnosis / Q000235:genetics*; D028901:alpha Karyopherins / Q000737:chemistry / Q000235:genetics*
chemical_list: C587929:KPNA7 protein, human; D028901:alpha Karyopherins
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