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-b 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-b. 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.

Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients

“…; Paciorkowski et al. ),and from our own earlier experiments. More information on many of the genes may also be found on: http://122.228.158.106/EpilepsyGene/index.php.We included known genes for EIEE from OMIM as well.…”

“…Recessive diseases are often, though not always, caused by inherited variants, and even more stringent criteria for pathogenicity should be applied. In many recent publications homozygous or compound heterozygous hits have been found in two or three sibs only (Simpson et al 2004;Banne et al 2013;Basel-Vanagaite et al 2013;Paciorkowski et al 2014), which is not statistically convincing. Here too, additional support is required.…”

“…; Paciorkowski et al. ), which is not statistically convincing. Here too, additional support is required.…”

“…Genes were collected up to a footprint of~1.2 Mb. We collected genes from the following studies: (Simpson et al 2004;Striano et al 2007;Backx et al 2009;Janer et al 2012;Banne et al 2013;Basel-Vanagaite et al 2013;Carvill et al 2013;Fr€ uhmesser et al 2013;Kodera et al 2013;Ohba et al 2013;Veeramah et al 2013;Consortium et al 2014;Paciorkowski et al 2014),and from our own earlier experiments. More information on many of the genes may also be found on: http://122.228.158.106/Epi-lepsyGene/index.php.We included known genes for EIEE from OMIM as well.…”

Diversification of importin-α isoforms in cellular trafficking and disease states

“…Analysis of the expression of importin-α isoforms in different regions of the mouse brain between birth and adulthood shows a distinct shift in levels and ratios of importin-α isoform expression [59]. A mutation in human importin α8 has also been found to be associated with improper neuronal development [116]. However, the redundancy of the importin-α isoforms still allows for proper brain development even when one of these isoforms is lost, as seen when importin α5 was knocked down in mice [62].…”