An epilepsy-associated mutation in the nuclear import receptor KPNA7 reduces nuclear localization signal binding.

is a member of the Importin-α family of nuclear import receptors. Kduanyu15357 forms a complex with Importin-β and facilitates the translocation of signal-containing proteins from the cytoplasm to the nucleus. Exome sequencing of siblings with severe neurodevelopmental defects and clinical features of epilepsy identified two amino acid-altering mutations in Here, we show that the E344Q substitution reduces Kduanyu15357 binding to nuclear localization signals, and that this limits Kduanyu15357 nuclear import activity. The P339A substitution, by contrast, has little effect on Kduanyu15357 binding to nuclear localization signals. Given the neuronal phenotype described in the two patients, we used SILAC labeling, affinity enrichment, and mass spectrometry to identify proteins in human induced pluripotent stem cell-derived neurons. We identified heterogeneous nuclear ribonucleoproteins hnRNP R and hnRNP U as Kduanyu15357-interacting proteins. The E344Q substitution reduced binding and import of these cargoes. The c.1030G > C allele which generates E344Q is within a predicted CTCF binding site, and we found that it reduces CTCF binding by approximately 40-fold. Our data support a role for altered neuronal expression and activity of Kduanyu15357 in a rare type of pediatric epilepsy.

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