-
Something wrong with this record ?
Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment
SK. Fiordaliso, A. Iwata-Otsubo, AL. Ritter, M. Quesnel-Vallières, K. Fujiki, E. Nishi, M. Hancarova, N. Miyake, JEV. Morton, S. Lee, K. Hackmann, M. Bando, K. Masuda, R. Nakato, M. Arakawa, E. Bhoj, D. Li, H. Hakonarson, R. Takeda, M. Harr, B....
Language English Country United States
Document type Journal Article
Grant support
U54 HD086984
NICHD NIH HHS - United States
NV17-29423A
MZ0
CEP Register
Digital library NLK
Full text - Article
NLK
Cell Press Free Archives
from 1997-01-01 to 6 months ago
Free Medical Journals
from 1949 to 6 months ago
PubMed Central
from 1949 to 6 months ago
Europe PubMed Central
from 1949 to 6 months ago
Open Access Digital Library
from 2005-01-01
- MeSH
- Zebrafish genetics MeSH
- Down-Regulation genetics MeSH
- Exons genetics MeSH
- Transcription, Genetic genetics MeSH
- Genes, X-Linked genetics MeSH
- Histone Deacetylases genetics MeSH
- Cognitive Dysfunction genetics MeSH
- Humans MeSH
- Mutation, Missense genetics MeSH
- Gene Expression Regulation genetics MeSH
- Repressor Proteins genetics MeSH
- Amino Acid Sequence MeSH
- Sequence Alignment MeSH
- Transcriptome genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
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.
Center for Applied Genomics The Children's Hospital of Philadelphia Philadelphia PA 19104 USA
Department of Medical Genetics Osaka Women's and Children's Hospital Osaka 594 1101 Japan
Department of Medical Genetics University Hospital Trencin Trencin 91171 Slovakia
Department of Pediatrics Seoul National University College of Medicine Seoul 03080 Republic of Korea
Division of Medical Genetics Nagano Children's Hospital Azumino 399 8205 Japan
Institute for Clinical Genetics TU Dresden Dresden 01307 Germany
Medical Genetics Unit Policlinico Sant'Orsola Malpighi University of Bologna Bologna 40138 Italy
Zebrafish Core Facility The Children's Hospital of Philadelphia Philadelphia PA 19104 USA
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc20023496
- 003
- CZ-PrNML
- 005
- 20201214130208.0
- 007
- ta
- 008
- 201125s2019 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1016/j.ajhg.2019.09.009 $2 doi
- 035 __
- $a (PubMed)31587868
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a Fiordaliso, Sarah K $u Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
- 245 10
- $a Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment / $c SK. Fiordaliso, A. Iwata-Otsubo, AL. Ritter, M. Quesnel-Vallières, K. Fujiki, E. Nishi, M. Hancarova, N. Miyake, JEV. Morton, S. Lee, K. Hackmann, M. Bando, K. Masuda, R. Nakato, M. Arakawa, E. Bhoj, D. Li, H. Hakonarson, R. Takeda, M. Harr, B. Keena, EH. Zackai, N. Okamoto, S. Mizuno, JM. Ko, A. Valachova, D. Prchalova, M. Vlckova, T. Pippucci, C. Seiler, M. Choi, N. Matsumoto, N. Di Donato, Y. Barash, Z. Sedlacek, K. Shirahige, K. Izumi,
- 520 9_
- $a 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.
- 650 _2
- $a sekvence aminokyselin $7 D000595
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a kognitivní dysfunkce $x genetika $7 D060825
- 650 _2
- $a down regulace $x genetika $7 D015536
- 650 _2
- $a exony $x genetika $7 D005091
- 650 _2
- $a regulace genové exprese $x genetika $7 D005786
- 650 _2
- $a geny vázané na chromozom X $x genetika $7 D050172
- 650 _2
- $a histondeacetylasy $x genetika $7 D006655
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a missense mutace $x genetika $7 D020125
- 650 _2
- $a represorové proteiny $x genetika $7 D012097
- 650 _2
- $a sekvenční seřazení $7 D016415
- 650 _2
- $a genetická transkripce $x genetika $7 D014158
- 650 _2
- $a transkriptom $x genetika $7 D059467
- 650 _2
- $a dánio pruhované $x genetika $7 D015027
- 655 _2
- $a časopisecké články $7 D016428
- 700 1_
- $a Iwata-Otsubo, Aiko $u Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
- 700 1_
- $a Ritter, Alyssa L $u Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
- 700 1_
- $a Quesnel-Vallières, Mathieu $u Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
- 700 1_
- $a Fujiki, Katsunori $u Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-8657, Japan.
- 700 1_
- $a Nishi, Eriko $u Division of Medical Genetics, Nagano Children's Hospital, Azumino 399-8205, Japan.
- 700 1_
- $a Hancarova, Miroslava $u Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague 15006, Czech Republic.
- 700 1_
- $a Miyake, Noriko $u Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
- 700 1_
- $a Morton, Jenny E V $u West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Edbaston, Birmingham B15 2TG, UK.
- 700 1_
- $a Lee, Sangmoon $u Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
- 700 1_
- $a Hackmann, Karl $u Institute for Clinical Genetics, TU Dresden, Dresden 01307, Germany.
- 700 1_
- $a Bando, Masashige $u Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-8657, Japan.
- 700 1_
- $a Masuda, Koji $u Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-8657, Japan.
- 700 1_
- $a Nakato, Ryuichiro $u Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-8657, Japan.
- 700 1_
- $a Arakawa, Michiko $u Division of Medical Genetics, Nagano Children's Hospital, Azumino 399-8205, Japan.
- 700 1_
- $a Bhoj, Elizabeth $u Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
- 700 1_
- $a Li, Dong $u Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
- 700 1_
- $a Hakonarson, Hakon $u Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
- 700 1_
- $a Takeda, Ryojun $u Division of Medical Genetics, Nagano Children's Hospital, Azumino 399-8205, Japan.
- 700 1_
- $a Harr, Margaret $u Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
- 700 1_
- $a Keena, Beth $u Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
- 700 1_
- $a Zackai, Elaine H $u Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
- 700 1_
- $a Okamoto, Nobuhiko $u Department of Medical Genetics, Osaka Women's and Children's Hospital, Osaka 594-1101, Japan.
- 700 1_
- $a Mizuno, Seiji $u Department of Clinical Genetics, Central Hospital, Aichi Developmental Disability Center, Aichi 480-0304, Japan.
- 700 1_
- $a Ko, Jung Min $u Department of Pediatrics, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
- 700 1_
- $a Valachova, Alica $u Department of Medical Genetics, University Hospital Trencin, Trencin 91171, Slovakia.
- 700 1_
- $a Prchalova, Darina $u Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague 15006, Czech Republic.
- 700 1_
- $a Vlckova, Marketa $u Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague 15006, Czech Republic.
- 700 1_
- $a Pippucci, Tommaso $u Medical Genetics Unit, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna 40138, Italy.
- 700 1_
- $a Seiler, Christoph $u Zebrafish Core Facility, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
- 700 1_
- $a Choi, Murim $u Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Pediatrics, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
- 700 1_
- $a Matsumoto, Naomichi $u Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
- 700 1_
- $a Di Donato, Nataliya $u Institute for Clinical Genetics, TU Dresden, Dresden 01307, Germany.
- 700 1_
- $a Barash, Yoseph $u Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
- 700 1_
- $a Sedlacek, Zdenek $u Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague 15006, Czech Republic.
- 700 1_
- $a Shirahige, Katsuhiko $u Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-8657, Japan.
- 700 1_
- $a Izumi, Kosuke $u Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Laboratory of Rare Disease Research, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-8657, Japan. Electronic address: izumik1@email.chop.edu.
- 773 0_
- $w MED00000254 $t American journal of human genetics $x 1537-6605 $g Roč. 105, č. 5 (2019), s. 987-995
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/31587868 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y a $z 0
- 990 __
- $a 20201125 $b ABA008
- 991 __
- $a 20201214130206 $b ABA008
- 999 __
- $a ok $b bmc $g 1595815 $s 1114172
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2019 $b 105 $c 5 $d 987-995 $e 20191003 $i 1537-6605 $m American journal of human genetics $n Am J Hum Genet $x MED00000254
- GRA __
- $a U54 HD086984 $p NICHD NIH HHS $2 United States
- GRA __
- $a NV17-29423A $p MZ0
- LZP __
- $a Pubmed-20201125
