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

Sofie Symoens; Aileen M. Barnes; Charlotte Gistelinck; Fransiska Malfait; Brecht Guillemyn; Wouter Steyaert; Delfien Syx; Sanne D'Hondt; Martine Biervliet; Julie De Backer; Eckhard P. Witten; Sergey Leikin; Elena Makareeva; Gabriele Gillessen-Kaesbach; Ann Huysseune; Kris Vleminckx; Andy Willaert; Anne De Paepe; Joan C. Marini; Paul J. Coucke

doi:10.1016/j.ajhg.2015.08.009

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

Sofie Symoens, Aileen M. Barnes, Charlotte Gistelinck, Fransiska Malfait, Brecht Guillemyn, Wouter Steyaert, Delfien Syx, Sanne D'Hondt, Martine Biervliet, Julie De Backer, Eckhard P. Witten, Sergey Leikin, Elena Makareeva, Gabriele Gillessen-Kaesbach, Ann Huysseune, Kris Vleminckx, Andy Willaert, Anne De Paepe, Joan C. Marini, Paul J. Coucke^*

^*Corresponding author for this work

Institute of Human Genetics

41 Citations (Scopus)

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.

Original language	English
Journal	American Journal of Human Genetics
Volume	97
Issue number	4
Pages (from-to)	521-534
Number of pages	14
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2015.08.009
Publication status	Published - 2015

Funding

We wish to thank P. Tapaneeyaphan, J. Weytens, P. Vermassen, L. Demuynck, P. Simoens, H. De Saffel and M. Soenens for excellent technical assistance. We are grateful to E. Parthoens and Dr. C. Guérin for access to the BioImaging Core, Ghent Platform, VIB. A.M.B. and J.C.M. acknowledge the NICHD Microscopy and Imaging Core. F.M. is a senior clinical investigator at the Fund for Scientific Research-Flanders. Contract grants include FWO grant number G.0171.05 to A.D.P. and Methusalem grant number 08/01M01108 to A.D.P. and NICHD, NIH Intramural Funding went to J.C.M. This work was also supported by funding from the Belgian Science Policy Office Interuniversity Attraction Poles (BELSPO-IAP) program through the project IAP P7/43-BeMGI. The Leica TCS LSI Super Zoom confocal microscope is supported by the Hercules Foundation, Flanders (grant AUGE/11/14).

Research Areas and Centers

Research Area: Medical Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ajhg.2015.08.009

Cite this

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. (2015). Genetic Defects in TAPT1 Disrupt Ciliogenesis and Cause a Complex Lethal Osteochondrodysplasia. American Journal of Human Genetics, 97(4), 521-534. https://doi.org/10.1016/j.ajhg.2015.08.009

@article{a42b3f92b4e54a86bb5465cec7d0a36a,

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.",

author = "Sofie Symoens and Barnes, \{Aileen M.\} and Charlotte Gistelinck and Fransiska Malfait and Brecht Guillemyn and Wouter Steyaert and Delfien Syx and Sanne D'Hondt and Martine Biervliet and \{De Backer\}, Julie and Witten, \{Eckhard P.\} and Sergey Leikin and Elena Makareeva and Gabriele Gillessen-Kaesbach and Ann Huysseune and Kris Vleminckx and Andy Willaert and \{De Paepe\}, Anne and Marini, \{Joan C.\} and Coucke, \{Paul J.\}",

year = "2015",

doi = "10.1016/j.ajhg.2015.08.009",

language = "English",

volume = "97",

pages = "521--534",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

}

Symoens, S, Barnes, AM, Gistelinck, C, Malfait, F, Guillemyn, B, Steyaert, W, Syx, D, D'Hondt, S, Biervliet, M, De Backer, J, Witten, EP, Leikin, S, Makareeva, E, Gillessen-Kaesbach, G, Huysseune, A, Vleminckx, K, Willaert, A, De Paepe, A, Marini, JC & Coucke, PJ 2015, 'Genetic Defects in TAPT1 Disrupt Ciliogenesis and Cause a Complex Lethal Osteochondrodysplasia', American Journal of Human Genetics, vol. 97, no. 4, pp. 521-534. https://doi.org/10.1016/j.ajhg.2015.08.009

TY - JOUR

T1 - Genetic Defects in TAPT1 Disrupt Ciliogenesis and Cause a Complex Lethal Osteochondrodysplasia

AU - Symoens, Sofie

AU - Barnes, Aileen M.

AU - Gistelinck, Charlotte

AU - Malfait, Fransiska

AU - Guillemyn, Brecht

AU - Steyaert, Wouter

AU - Syx, Delfien

AU - D'Hondt, Sanne

AU - Biervliet, Martine

AU - De Backer, Julie

AU - Witten, Eckhard P.

AU - Leikin, Sergey

AU - Makareeva, Elena

AU - Gillessen-Kaesbach, Gabriele

AU - Huysseune, Ann

AU - Vleminckx, Kris

AU - Willaert, Andy

AU - De Paepe, Anne

AU - Marini, Joan C.

AU - Coucke, Paul J.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84952717439

U2 - 10.1016/j.ajhg.2015.08.009

DO - 10.1016/j.ajhg.2015.08.009

M3 - Journal articles

C2 - 26365339

AN - SCOPUS:84952717439

SN - 0002-9297

VL - 97

SP - 521

EP - 534

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

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

Abstract

Funding

Research Areas and Centers

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this