PUBLICATION
Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment
- Authors
- Fiordaliso, S.K., Iwata-Otsubo, A., Ritter, A.L., Quesnel-Vallières, M., Fujiki, K., Nishi, E., Hancarova, M., Miyake, N., Morton, J.E.V., Lee, S., Hackmann, K., Bando, M., Masuda, K., Nakato, R., Arakawa, M., Bhoj, E., Li, D., Hakonarson, H., Takeda, R., Harr, M., Keena, B., Zackai, E.H., Okamoto, N., Mizuno, S., Ko, J.M., Valachova, A., Prchalova, D., Vlckova, M., Pippucci, T., Seiler, C., Choi, M., Matsumoto, N., Di Donato, N., Barash, Y., Sedlacek, Z., Shirahige, K., Izumi, K.
- ID
- ZDB-PUB-191008-1
- Date
- 2019
- Source
- American journal of human genetics 105(5): 987-995 (Journal)
- Registered Authors
- Keywords
- P-complex, spliceosome, splicing, transcriptome
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Cognitive Dysfunction/genetics*
- Down-Regulation/genetics
- Exons/genetics
- Gene Expression Regulation/genetics
- Genes, X-Linked/genetics
- Histone Deacetylases/genetics
- Humans
- Mutation, Missense/genetics*
- Repressor Proteins/genetics*
- Sequence Alignment
- Transcription, Genetic/genetics*
- Transcriptome/genetics
- Zebrafish/genetics
- PubMed
- 31587868 Full text @ Am. J. Hum. Genet.
Citation
Fiordaliso, S.K., Iwata-Otsubo, A., Ritter, A.L., Quesnel-Vallières, M., Fujiki, K., Nishi, E., Hancarova, M., Miyake, N., Morton, J.E.V., Lee, S., Hackmann, K., Bando, M., Masuda, K., Nakato, R., Arakawa, M., Bhoj, E., Li, D., Hakonarson, H., Takeda, R., Harr, M., Keena, B., Zackai, E.H., Okamoto, N., Mizuno, S., Ko, J.M., Valachova, A., Prchalova, D., Vlckova, M., Pippucci, T., Seiler, C., Choi, M., Matsumoto, N., Di Donato, N., Barash, Y., Sedlacek, Z., Shirahige, K., Izumi, K. (2019) Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment. American journal of human genetics. 105(5):987-995.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping