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

Publication ,  Journal Article
Lee, CS; Fu, H; Baratang, N; Rousseau, J; Kumra, H; Sutton, VR; Niceta, M; Ciolfi, A; Yamamoto, G; Bertola, D; Marcelis, CL; Lugtenberg, D ...
Published in: Am J Hum Genet
November 2, 2017

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.

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Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

November 2, 2017

Volume

101

Issue

5

Start / End Page

815 / 823

Location

United States

Related Subject Headings

  • Scoliosis
  • Phenotype
  • Osteochondrodysplasias
  • Mutation
  • Male
  • Humans
  • Genetics & Heredity
  • Fractures, Bone
  • Fibronectins
  • Female
 

Citation

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Lee, C. S., Fu, H., Baratang, N., Rousseau, J., Kumra, H., Sutton, V. R., … Campeau, P. M. (2017). Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures". Am J Hum Genet, 101(5), 815–823. https://doi.org/10.1016/j.ajhg.2017.09.019
Lee, Chae Syng, He Fu, Nissan Baratang, Justine Rousseau, Heena Kumra, V Reid Sutton, Marcello Niceta, et al. “Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".Am J Hum Genet 101, no. 5 (November 2, 2017): 815–23. https://doi.org/10.1016/j.ajhg.2017.09.019.
Lee CS, Fu H, Baratang N, Rousseau J, Kumra H, Sutton VR, et al. Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures". Am J Hum Genet. 2017 Nov 2;101(5):815–23.
Lee, Chae Syng, et al. “Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".Am J Hum Genet, vol. 101, no. 5, Nov. 2017, pp. 815–23. Pubmed, doi:10.1016/j.ajhg.2017.09.019.
Lee CS, Fu H, Baratang N, Rousseau J, Kumra H, Sutton VR, Niceta M, Ciolfi A, Yamamoto G, Bertola D, Marcelis CL, Lugtenberg D, Bartuli A, Kim C, Hoover-Fong J, Sobreira N, Pauli R, Bacino C, Krakow D, Parboosingh J, Yap P, Kariminejad A, McDonald MT, Aracena MI, Lausch E, Unger S, Superti-Furga A, Lu JT, Baylor-Hopkins Center for Mendelian Genomics, Cohn DH, Tartaglia M, Lee BH, Reinhardt DP, Campeau PM. Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures". Am J Hum Genet. 2017 Nov 2;101(5):815–823.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

November 2, 2017

Volume

101

Issue

5

Start / End Page

815 / 823

Location

United States

Related Subject Headings

  • Scoliosis
  • Phenotype
  • Osteochondrodysplasias
  • Mutation
  • Male
  • Humans
  • Genetics & Heredity
  • Fractures, Bone
  • Fibronectins
  • Female