Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".

Détails

ID Serval
serval:BIB_D12E5334C4E8
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".
Périodique
American journal of human genetics
Auteur(s)
Lee C.S., Fu H., Baratang N., Rousseau J., Kumra H., Sutton V.R., Niceta M., Ciolfi A., Yamamoto G., Bertola D., Marcelis C.L., Lugtenberg D., Bartuli A., Kim C., Hoover-Fong J., Sobreira N., Pauli R., Bacino C., Krakow D., Parboosingh J., Yap P., Kariminejad A., McDonald M.T., Aracena M.I., Lausch E., Unger S., Superti-Furga A., Lu J.T., Cohn D.H., Tartaglia M., Lee B.H., Reinhardt D.P., Campeau P.M.
Collaborateur(s)
Baylor-Hopkins Center for Mendelian Genomics
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Statut éditorial
Publié
Date de publication
02/11/2017
Peer-reviewed
Oui
Volume
101
Numéro
5
Pages
815-823
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of "corner fractures" at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70 kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.

Mots-clé
Adolescent, Adult, Bone Diseases, Developmental/genetics, Bone and Bones/pathology, Cartilage/pathology, Child, Child, Preschool, Exome/genetics, Female, Fibronectins/genetics, Fractures, Bone/genetics, Humans, Male, Mutation/genetics, Osteochondrodysplasias/genetics, Phenotype, Scoliosis/genetics, FN1, cartilage, corner fractures, extracellular matrix, fibronectin, metaphyses, protein secretion, scoliosis, skeletal dysplasia, spondylometaphyseal
Pubmed
Web of science
Création de la notice
22/11/2017 12:05
Dernière modification de la notice
03/03/2018 21:37
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