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 Biology and Medical Genetics 2nd Faculty of Medicine and University Hospital Motol Charles University Prague 15006 Czech Republic

Department of Biomedical Sciences Seoul National University College of Medicine Seoul 03080 Republic of Korea

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

Department of Clinical Genetics Central Hospital Aichi Developmental Disability Center Aichi 480 0304 Japan

Department of Genetics Perelman School of Medicine at the University of Pennsylvania Philadelphia PA 19104 USA

Department of Human Genetics Yokohama City University Graduate School of Medicine Yokohama 236 0004 Japan

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 Human Genetics Department of Pediatrics The Children's Hospital of Philadelphia Philadelphia PA 19104 USA

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 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

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

Division of Medical Genetics Nagano Children's Hospital Azumino 399 8205 Japan

Institute for Clinical Genetics TU Dresden Dresden 01307 Germany

Laboratory of Genome Structure and Function Institute for Quantitative Biosciences The University of Tokyo Tokyo 113 8657 Japan

Medical Genetics Unit Policlinico Sant'Orsola Malpighi University of Bologna Bologna 40138 Italy

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

Zebrafish Core Facility The Children's Hospital of Philadelphia Philadelphia PA 19104 USA

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