PUBLICATION
Genetic Defects in TAPT1 Disrupt Ciliogenesis and Cause a Complex Lethal Osteochondrodysplasia
- Authors
- Symoens, S., Barnes, A.M., Gistelinck, C., Malfait, F., Guillemyn, B., Steyaert, W., Syx, D., D'hondt, S., Biervliet, M., De Backer, J., Witten, E.P., Leikin, S., Makareeva, E., Gillessen-Kaesbach, G., Huysseune, A., Vleminckx, K., Willaert, A., De Paepe, A., Marini, J.C., Coucke, P.J.
- ID
- ZDB-PUB-150916-17
- Date
- 2015
- Source
- American journal of human genetics 97(4): 521-34 (Journal)
- Registered Authors
- Coucke, Paul, Huysseune, Ann, Willaert, Andy, Witten, P. Eckhard
- Keywords
- none
- MeSH Terms
-
- Pedigree
- In Situ Hybridization
- Craniofacial Abnormalities/genetics*
- Gene Expression Regulation, Developmental
- Molecular Sequence Data
- PubMed
- 26365339 Full text @ Am. J. Hum. Genet.
Abstract
The evolutionarily conserved transmembrane anterior posterior transformation 1 protein, encoded by TAPT1, is involved in murine axial skeletal patterning, but its cellular function remains unknown. Our study demonstrates that TAPT1 mutations underlie a complex congenital syndrome, showing clinical overlap between lethal skeletal dysplasias and ciliopathies. This syndrome is characterized by fetal lethality, severe hypomineralization of the entire skeleton and intra-uterine fractures, and multiple congenital developmental anomalies affecting the brain, lungs, and kidneys. We establish that wild-type TAPT1 localizes to the centrosome and/or ciliary basal body, whereas defective TAPT1 mislocalizes to the cytoplasm and disrupts Golgi morphology and trafficking and normal primary cilium formation. Knockdown of tapt1b in zebrafish induces severe craniofacial cartilage malformations and delayed ossification, which is shown to be associated with aberrant differentiation of cranial neural crest cells.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping