Busca avançada
Ano de início
Entree
(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

Texto completo
Autor(es):
Mostrar menos -
Lee, Chae Syng [1, 2] ; Fu, He [3] ; Baratang, Nissan [3] ; Rousseau, Justine [3] ; Kumra, Heena [2, 1] ; Sutton, V. Reid [4] ; Niceta, Marcello [5] ; Ciolfi, Andrea [5] ; Yamamoto, Guilherme [6] ; Bertola, Debora [6] ; Marcelis, Carlo L. [7, 8] ; Lugtenberg, Dorien [7, 8] ; Bartuli, Andrea [5] ; Kim, Choel ; Hoover-Fong, Julie [9] ; Sobreira, Nara [9] ; Pauli, Richard [10] ; Bacino, Carlos [4] ; Krakow, Deborah [11] ; Parboosingh, Jillian [12, 13] ; Yap, Patrick [14] ; Kariminejad, Ariana [15] ; McDonald, Marie T. [16] ; Aracena, Mariana I. [17] ; Lausch, Ekkehart [18] ; Unger, Sheila [19] ; Superti-Furga, Andrea [19] ; Lu, James T. [20] ; Cohn, Dan H. [21] ; Tartaglia, Marco [5] ; Lee, Brendan H. [4] ; Reinhardt, Dieter P. [1] ; Campeau, Philippe M. [3] ; Mendelian, Baylor-Hopkins Ctr
Número total de Autores: 34
Afiliação do(s) autor(es):
Mostrar menos -
[1] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ H3A 0C7 - Canada
[2] McGill Univ, Fac Dent, Montreal, PQ H3A 0C7 - Canada
[3] Univ Montreal, Ctr Hosp Univ St Justine Res Ctr, Montreal, PQ H3T 1C5 - Canada
[4] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 - USA
[5] Bambino Gesu Pediat Hosp, Ist Ricovero & Cura Carattere Sci, Genet & Rare Dis Res Div, I-00146 Rome - Italy
[6] Univ Sao Paulo, Fac Med, Hosp Clin, Clin Genet, Unit Inst Crianca, BR-05403000 Sao Paulo, SP - Brazil
[7] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen - Netherlands
[8] Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 - USA
[9] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21287 - USA
[10] Univ Wisconsin, Midwest Reg Bone Dysplasia Clin, Madison, WI 53705 - USA
[11] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 - USA
[12] Univ Calgary, Dept Med Genet, Calgary, AB T2N 4N1 - Canada
[13] Univ Calgary, Alberta Childrens Hosp Res Inst, Calgary, AB T2N 4N1 - Canada
[14] Genet Hlth Serv New Zealand Northern Hub, Auckland 1023 - New Zealand
[15] Kariminejad Najmabadi Pathol & Genet Ctr, Tehran 14665 - Iran
[16] Duke Univ, Med Ctr, Div Med Genet, Dept Pediat, Durham, NC 27710 - USA
[17] Pontificia Univ Catolica Chile, Hosp Dr Luis Calvo Mackenna, Unidad Genet, Div Pediat, Pediatra Genetista, Santiago - Chile
[18] Univ Freiburg, Dept Pediat, Med Ctr, D-79106 Freiburg - Germany
[19] Lausanne Univ Hosp CHUV, Serv Med Genet, CH-1011 Lausanne - Switzerland
[20] Helix, San Carlos, CA 94070 - USA
[21] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 - USA
Número total de Afiliações: 21
Tipo de documento: Artigo Científico
Fonte: American Journal of Human Genetics; v. 101, n. 5, p. 815-823, NOV 2 2017.
Citações Web of Science: 8
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. (AU)

Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
Beneficiário:Mayana Zatz
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
Processo FAPESP: 15/21783-9 - Pesquisa de variantes genéticas nas osteocondrodisplasias raras pela técnica do sequenciamento do exoma completo
Beneficiário:Débora Romeo Bertola
Linha de fomento: Auxílio à Pesquisa - Regular