Paciorkowski Alex R, Weisenberg Judy, Kelley Joshua B, Spencer Adam, Tuttle Emily, Ghoneim Dalia, Thio Liu Lin, Christian Susan L, Dobyns William B, Paschal Bryce M
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.
Departments of Neurology and Pediatrics, Pediatric Epilepsy Center, Washington University, St Louis, MO, USA.
Eur J Hum Genet. 2014 May;22(5):587-93. doi: 10.1038/ejhg.2013.196. Epub 2013 Sep 18.
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.
KPNA家族的核输入受体可识别蛋白质中的核定位信号，并与输入蛋白β一起介导蛋白转运进入细胞核。因此，KPNA家族成员具有高度保守的结构，其结构域可与核定位信号接触并与输入蛋白β结合。在此，我们描述了通过全外显子组测序在一对患有严重发育障碍、婴儿痉挛症、随后出现与Lennox-Gastaut综合征一致的难治性癫痫、胼胝体部分发育不全和小脑蚓部发育不全的同胞中发现的KPNA7常染色体隐性突变。这些突变定位于KPNA7的外显子7，导致两个氨基酸替换，即Pro339Ala和Glu344Gln。根据与视网膜母细胞瘤蛋白的二分核定位信号结合的旁系同源物KPNA2的晶体结构，预测受影响个体中的氨基酸替换发生在形成KPNA家族成员中两个核定位信号结合位点之一的第七个犰狳重复序列内。Glu344在所有七种KPNA蛋白中都是保守的，我们发现KPNA2中的Glu354Gln突变足以将与视网膜母细胞瘤核定位信号的结合降低至野生型蛋白的约二分之一。我们的数据表明，KPNA7中的复合杂合突变与一种人类神经发育疾病相关，并提供了与核转运受体突变相关的人类疾病的首个实例。
