ZFIN ID: ZDB-PUB-150916-17
Genetic Defects in TAPT1 Disrupt Ciliogenesis and Cause a Complex Lethal Osteochondrodysplasia
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.
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:
  • Amino Acid Sequence
  • Animals
  • Body Patterning
  • Cell Differentiation
  • Cell Movement
  • Cilia/genetics*
  • Cilia/metabolism
  • Cilia/pathology
  • Ciliary Motility Disorders/genetics*
  • Craniofacial Abnormalities/genetics*
  • Embryo, Nonmammalian/abnormalities
  • Female
  • Gene Expression Regulation, Developmental
  • Humans
  • In Situ Hybridization
  • Male
  • Membrane Proteins/genetics*
  • Membrane Proteins/metabolism
  • Molecular Sequence Data
  • Mutation/genetics*
  • Neural Crest/cytology
  • Neural Crest/metabolism
  • Ossification, Heterotopic/genetics*
  • Osteochondrodysplasias/genetics*
  • Pedigree
  • Protein Transport
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Zebrafish/embryology
  • Zebrafish/genetics
PubMed: 26365339 Full text @ Am. J. Hum. Genet.
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.