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

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art_LEE_Mutations_in_Fibronectin_Cause_a_Subtype_of_Spondylometaphyseal_2017.PDF (2.02 MB)
Citações na Scopus
35
Tipo de produção
article
Data de publicação
2017
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
CELL PRESS
Autores
LEE, Chae Syng
FU, He
BARATANG, Nissan
ROUSSEAU, Justine
KUMRA, Heena
SUTTON, V. Reid
NICETA, Marcello
CIOLFI, Andrea
Citação
AMERICAN JOURNAL OF HUMAN GENETICS, v.101, n.5, p.815-823, 2017
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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. Spondylo-metaphyseal 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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URI
https://observatorio.fm.usp.br/handle/OPI/24428
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Coleções
Artigos e Materiais de Revistas Científicas - HC/ICr
Artigos e Materiais de Revistas Científicas - LIM/36