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Am J Hum Genet. 2019 Nov 7;105(5):987-995. doi: 10.1016/j.ajhg.2019.09.009. Epub 2019 Oct 3.

Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment.

Author information

1
Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
2
Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-8657, Japan.
4
Division of Medical Genetics, Nagano Children's Hospital, Azumino 399-8205, Japan.
5
Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague 15006, Czech Republic.
6
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
7
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.
8
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
9
Institute for Clinical Genetics, TU Dresden, Dresden 01307, Germany.
10
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.
11
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
12
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.
13
Department of Medical Genetics, Osaka Women's and Children's Hospital, Osaka 594-1101, Japan.
14
Department of Clinical Genetics, Central Hospital, Aichi Developmental Disability Center, Aichi 480-0304, Japan.
15
Department of Pediatrics, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
16
Department of Medical Genetics, University Hospital Trencin, Trencin 91171, Slovakia.
17
Medical Genetics Unit, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna 40138, Italy.
18
Zebrafish Core Facility, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
19
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.
20
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.

Abstract

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.

KEYWORDS:

P-complex; spliceosome; splicing; transcriptome

PMID:
31587868
PMCID:
PMC6848994
[Available on 2020-05-07]
DOI:
10.1016/j.ajhg.2019.09.009

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