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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Lee, Chae Syng [1, 2] ; Fu, He [3] ; Baratang, Nissan [3] ; Rousseau, Justine [3] ; Kumra, Heena [1, 2] ; 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
Total Authors: 34
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[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
Total Affiliations: 21
Document type: Journal article
Source: American Journal of Human Genetics; v. 101, n. 5, p. 815-823, NOV 2 2017.
Web of Science Citations: 9

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)

FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
Grantee:Mayana Zatz
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 15/21783-9 - Analysis of genetic variants in rare osteochondrodysplasias using whole exome sequencing
Grantee:Débora Romeo Bertola
Support type: Regular Research Grants