Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment
| Autor: | Sangmoon Lee, Ryojun Takeda, Nataliya Di Donato, Masashige Bando, Darina Prchalova, Mathieu Quesnel-Vallières, Seiji Mizuno, Naomichi Matsumoto, Koji Masuda, Miroslava Hancarova, Margaret Harr, Karl Hackmann, Zdenek Sedlacek, Alica Valachova, Alyssa Ritter, Eriko Nishi, Tommaso Pippucci, Michiko Arakawa, Katsuhiko Shirahige, Katsunori Fujiki, Elaine H. Zackai, Noriko Miyake, Marketa Vlckova, Ryuichiro Nakato, Aiko Iwata-Otsubo, Yoseph Barash, Christoph Seiler, Dong Li, Beth Keena, Nobuhiko Okamoto, Kosuke Izumi, Jung Min Ko, Sarah K. Fiordaliso, Elizabeth J. Bhoj, Hakon Hakonarson, Murim Choi, Jenny Morton |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Transcription Genetic Mutation Missense Down-Regulation Biology Histone Deacetylases Transcriptome 03 medical and health sciences Exon 0302 clinical medicine Genes X-Linked Report Genetics Transcriptional regulation Animals Humans Missense mutation Cognitive Dysfunction Amino Acid Sequence Gene Zebrafish Genetics (clinical) X chromosome Spliceosomal complex Exons biology.organism_classification Repressor Proteins 030104 developmental biology Gene Expression Regulation Sequence Alignment 030217 neurology & neurosurgery |
| Zdroj: | Am J Hum Genet |
| ISSN: | 0002-9297 |
| Popis: | NKAP is a ubiquitously expressed nucleoplasmic protein that is currently known as a transcriptional regulatory molecule via its interaction with HDAC3 and spliceosomal proteins. Here, we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP. These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins. Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects. The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis. In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers. These observations indicate the critical role of NKAP in transcriptional regulation and demonstrate that perturbations of the C-terminal region lead to developmental defects in both humans and zebrafish. |
| Databáze: | OpenAIRE |
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