title: Genetic Defects in TAPT1 Disrupt Ciliogenesis and Cause a Complex Lethal Osteochondrodysplasia.
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.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Symoens
authors.affiliation: Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Barnes
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gistelinck
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Fransiska
authors.initials: F
authors.lastname: Malfait
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Brecht
authors.initials: B
authors.lastname: Guillemyn
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Wouter
authors.initials: W
authors.lastname: Steyaert
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Delfien
authors.initials: D
authors.lastname: Syx
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Sanne
authors.initials: S
authors.lastname: D'hondt
authors.affiliation: Center for Medical Genetics, Brussels University Hospital, 1090 Brussels, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Biervliet
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: De Backer
authors.affiliation: Biology Department, Ghent University, 9000 Ghent, Belgium.
authors.forename: Eckhard P
authors.initials: EP
authors.lastname: Witten
authors.affiliation: Section on Physical Biochemistry, NICHD, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Leikin
authors.affiliation: Section on Physical Biochemistry, NICHD, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Makareeva
authors.affiliation: Institut für Humangenetik Lübeck, Universität zu Lübeck Schleswig-Holstein, 23538 Lübeck, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.affiliation: Biology Department, Ghent University, 9000 Ghent, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Huysseune
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Vleminckx
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Andy
authors.initials: A
authors.lastname: Willaert
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.affiliation: Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium. Electronic address: paul.coucke@ugent.be.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coucke
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019521:Body Patterning; D002454:Cell Differentiation; D002465:Cell Movement; D002923:Cilia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002925:Ciliary Motility Disorders / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000002:abnormalities; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism; D009999:Ossification, Heterotopic / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000235:genetics*; D010375:Pedigree; D021381:Protein Transport; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D008565:Membrane Proteins