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Am J Hum Genet. 2015 Oct 1;97(4):521-34. doi: 10.1016/j.ajhg.2015.08.009. Epub 2015 Sep 10.

Genetic Defects in TAPT1 Disrupt Ciliogenesis and Cause a Complex Lethal Osteochondrodysplasia.

Author information

1
Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
2
Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, Maryland 20892, USA.
3
Center for Medical Genetics, Brussels University Hospital, 1090 Brussels, Belgium.
4
Biology Department, Ghent University, 9000 Ghent, Belgium.
5
Section on Physical Biochemistry, NICHD, NIH, Bethesda, Maryland 20892, USA.
6
Institut für Humangenetik Lübeck, Universität zu Lübeck Schleswig-Holstein, 23538 Lübeck, Germany.
7
Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
8
Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium. Electronic address: paul.coucke@ugent.be.

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.

PMID:
26365339
PMCID:
PMC4596895
DOI:
10.1016/j.ajhg.2015.08.009
[Indexed for MEDLINE]
Free PMC Article

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