%0 Journal Article
%T Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with ˇ°Corner Fracturesˇ±
%A Andrea Bartuli
%A Andrea Ciolfi
%A Andrea Superti-Furga
%A Ariana Kariminejad
%A Baylor-Hopkins Center for Mendelian Genomics
%A Brendan H. Lee
%A Carlo L. Marcelis
%A Carlos Bacino
%A Chae Syng Lee
%A Choel Kim
%A Dan H. Cohn
%A Deborah Krakow
%A Dieter P. Reinhardt
%A Dorien Lugtenberg
%A D¨¦bora Bertola
%A Ekkehart Lausch
%A Guilherme Yamamoto
%A He Fu
%A Heena Kumra
%A James T. Lu
%A Jillian Parboosingh
%A Julie Hoover-Fong
%A Justine Rousseau
%A Marcello Niceta
%A Marco Tartaglia
%A Mariana I. Aracena
%A Marie T. McDonald
%A Nara Sobreira
%A Nissan Baratang
%A Patrick Yap
%A Richard Pauli
%A Sheila Unger
%A V. Reid Sutton
%J Archive of "American Journal of Human Genetics".
%D 2017
%R 10.1016/j.ajhg.2017.09.019
%X 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 ˇ°corner fracturesˇ± 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
%K fibronectin
%K extracellular matrix
%K skeletal dysplasia
%K spondylometaphyseal
%K scoliosis
%K cartilage
%K protein secretion
%K corner fractures
%K metaphyses
%K FN1
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673654/