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BBS9 gene in nonsyndromic craniosynostosis: Role of the primary cilium in the aberrant ossification of the suture osteogenic niche.
Bone 2018; 112:58-70BONE

Abstract

Nonsyndromic craniosynostosis (NCS) is the premature ossification of skull sutures, without associated clinical features. Mutations in several genes account for a small number of NCS patients; thus, the molecular etiopathogenesis of NCS remains largely unclear. Our study aimed at characterizing the molecular signaling implicated in the aberrant ossification of sutures in NCS patients. Comparative gene expression profiling of NCS patient sutures identified a fused suture-specific signature, including 17 genes involved in primary cilium signaling and assembly. Cells from fused sutures displayed a reduced potential to form primary cilia compared to cells from control patent sutures of the same patient. We identified specific upregulated splice variants of the Bardet Biedl syndrome-associated gene 9 (BBS9), which encodes a structural component of the ciliary BBSome complex. BBS9 expression increased during in vitro osteogenic differentiation of suture-derived mesenchymal cells of NCS patients. Also, Bbs9 expression increased during in vivo ossification of rat sutures. BBS9 functional knockdown affected the expression of primary cilia on patient suture cells and their osteogenic potential. Computational modeling of the upregulated protein isoforms (observed in patients) predicted that their binding affinity within the BBSome may be affected, providing a possible explanation for the aberrant suture ossification in NCS.

Authors+Show Affiliations

Istituto di Anatomia Umana e Biologia Cellulare, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; Fondazione Policlinico Universitario "Agostino Gemelli", 00168 Rome, Italy.Istituto di Anatomia Umana e Biologia Cellulare, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.Fondazione Policlinico Universitario "Agostino Gemelli", 00168 Rome, Italy; Istituto di Neurochirurgia, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.Istituto di Anatomia Umana e Biologia Cellulare, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; Fondazione Policlinico Universitario "Agostino Gemelli", 00168 Rome, Italy.Fondazione Policlinico Universitario "Agostino Gemelli", 00168 Rome, Italy.Fondazione Policlinico Universitario "Agostino Gemelli", 00168 Rome, Italy; Istituto di Neurochirurgia, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.Istituto di Anatomia Umana e Biologia Cellulare, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100, L'Aquila, Italy.Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, 52242, IA, USA.Department of Neurosurgery, International Neuroscience Institute, 30625 Hannover, Germany.Istituto di Neurochirurgia, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; Istituto di Biochimica e Biochimica Clinica, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.Istituto di Anatomia Umana e Biologia Cellulare, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; Fondazione Policlinico Universitario "Agostino Gemelli", 00168 Rome, Italy; Centro di Ricerca E. Menni, Fondazione Poliambulanza-Istituto Ospedaliero, 25124 Brescia, Italy.Fondazione Policlinico Universitario "Agostino Gemelli", 00168 Rome, Italy; Istituto di Neurochirurgia, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.Istituto di Anatomia Umana e Biologia Cellulare, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; Fondazione Policlinico Universitario "Agostino Gemelli", 00168 Rome, Italy.Section of Genomics, Department of Pediatrics, University of California, 95817 Sacramento, CA, USA.Istituto di Anatomia Umana e Biologia Cellulare, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; Fondazione Policlinico Universitario "Agostino Gemelli", 00168 Rome, Italy. Electronic address: wanda.lattanzi@unicatt.it.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29674126

Citation

Barba, Marta, et al. "BBS9 Gene in Nonsyndromic Craniosynostosis: Role of the Primary Cilium in the Aberrant Ossification of the Suture Osteogenic Niche." Bone, vol. 112, 2018, pp. 58-70.
Barba M, Di Pietro L, Massimi L, et al. BBS9 gene in nonsyndromic craniosynostosis: Role of the primary cilium in the aberrant ossification of the suture osteogenic niche. Bone. 2018;112:58-70.
Barba, M., Di Pietro, L., Massimi, L., Geloso, M. C., Frassanito, P., Caldarelli, M., ... Lattanzi, W. (2018). BBS9 gene in nonsyndromic craniosynostosis: Role of the primary cilium in the aberrant ossification of the suture osteogenic niche. Bone, 112, pp. 58-70. doi:10.1016/j.bone.2018.04.013.
Barba M, et al. BBS9 Gene in Nonsyndromic Craniosynostosis: Role of the Primary Cilium in the Aberrant Ossification of the Suture Osteogenic Niche. Bone. 2018;112:58-70. PubMed PMID: 29674126.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - BBS9 gene in nonsyndromic craniosynostosis: Role of the primary cilium in the aberrant ossification of the suture osteogenic niche. AU - Barba,Marta, AU - Di Pietro,Lorena, AU - Massimi,Luca, AU - Geloso,Maria Concetta, AU - Frassanito,Paolo, AU - Caldarelli,Massimo, AU - Michetti,Fabrizio, AU - Della Longa,Stefano, AU - Romitti,Paul A, AU - Di Rocco,Concezio, AU - Arcovito,Alessandro, AU - Parolini,Ornella, AU - Tamburrini,Gianpiero, AU - Bernardini,Camilla, AU - Boyadjiev,Simeon A, AU - Lattanzi,Wanda, Y1 - 2018/04/17/ PY - 2018/02/07/received PY - 2018/04/12/revised PY - 2018/04/14/accepted PY - 2018/4/21/pubmed PY - 2019/4/9/medline PY - 2018/4/21/entrez KW - BBS9 KW - Gene expression signatures KW - Innovative biotechnologies KW - Mesenchymal stromal cells KW - Nonsyndromic craniosynostosis KW - Primary cilium SP - 58 EP - 70 JF - Bone JO - Bone VL - 112 N2 - Nonsyndromic craniosynostosis (NCS) is the premature ossification of skull sutures, without associated clinical features. Mutations in several genes account for a small number of NCS patients; thus, the molecular etiopathogenesis of NCS remains largely unclear. Our study aimed at characterizing the molecular signaling implicated in the aberrant ossification of sutures in NCS patients. Comparative gene expression profiling of NCS patient sutures identified a fused suture-specific signature, including 17 genes involved in primary cilium signaling and assembly. Cells from fused sutures displayed a reduced potential to form primary cilia compared to cells from control patent sutures of the same patient. We identified specific upregulated splice variants of the Bardet Biedl syndrome-associated gene 9 (BBS9), which encodes a structural component of the ciliary BBSome complex. BBS9 expression increased during in vitro osteogenic differentiation of suture-derived mesenchymal cells of NCS patients. Also, Bbs9 expression increased during in vivo ossification of rat sutures. BBS9 functional knockdown affected the expression of primary cilia on patient suture cells and their osteogenic potential. Computational modeling of the upregulated protein isoforms (observed in patients) predicted that their binding affinity within the BBSome may be affected, providing a possible explanation for the aberrant suture ossification in NCS. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/29674126/BBS9_gene_in_nonsyndromic_craniosynostosis:_Role_of_the_primary_cilium_in_the_aberrant_ossification_of_the_suture_osteogenic_niche_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(18)30159-5 DB - PRIME DP - Unbound Medicine ER -