2. Academic Validation
  3. Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures"

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

  • Am J Hum Genet. 2017 Nov 2;101(5):815-823. doi: 10.1016/j.ajhg.2017.09.019.
Chae Syng Lee 1,  He Fu 2,  Nissan Baratang 2,  Justine Rousseau 2,  Heena Kumra 1,  V Reid Sutton 3,  Marcello Niceta 4,  Andrea Ciolfi 4,  Guilherme Yamamoto 5,  Débora Bertola 5,  Carlo L Marcelis 6,  Dorien Lugtenberg 6,  Andrea Bartuli 4,  Choel Kim 7,  Julie Hoover-Fong 8,  Nara Sobreira 8,  Richard Pauli 9,  Carlos Bacino 3,  Deborah Krakow 10,  Jillian Parboosingh 11,  Patrick Yap 12,  Ariana Kariminejad 13,  Marie T McDonald 14,  Mariana I Aracena 15,  Ekkehart Lausch 16,  Sheila Unger 17,  Andrea Superti-Furga 17,  James T Lu 18,  Baylor-Hopkins Center for Mendelian Genomics 19,  Dan H Cohn 20,  Marco Tartaglia 4,  Brendan H Lee 3,  Dieter P Reinhardt 21,  Philippe M Campeau 22
Affiliations

Affiliations

  • 1 Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada.
  • 2 Centre Hospitalier Universitaire Sainte Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada.
  • 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 4 Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome 00146, Italy.
  • 5 Clinical Genetics Unit, Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo SP 05403-000, Brazil.
  • 6 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
  • 7 Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 8 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 9 Midwest Regional Bone Dysplasia Clinic, University of Wisconsin, Madison, WI 53705, USA.
  • 10 Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 11 Department of Medical Genetics and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 12 Genetic Health Service New Zealand (Northern Hub), Auckland 1023, New Zealand.
  • 13 Kariminejad-Najmabadi Pathology & Genetics Center, Tehran 14665, Iran.
  • 14 Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC 27710, USA.
  • 15 División de Pediatría, Pontificia Universidad Católica de Chile, Pediatra-Genetista, Unidad de Genética, Hospital Dr. Luis Calvo Mackenna, Santiago, Chile.
  • 16 Department of Pediatrics, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.
  • 17 Service of Medical Genetics, Lausanne University Hospital (CHUV), Lausanne 1011, Switzerland.
  • 18 Helix, San Carlos, CA 94070, USA.
  • 19 Baylor-Hopkins Center for Mendelian Genomics, Houston, TX 77030, USA.
  • 20 Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 21 Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada. Electronic address: [email protected].
  • 22 Centre Hospitalier Universitaire Sainte Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address: [email protected].
PMID: 29100092 DOI: 10.1016/j.ajhg.2017.09.019
Abstract

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.

Keywords

FN1; cartilage; corner fractures; extracellular matrix; fibronectin; metaphyses; protein secretion; scoliosis; skeletal dysplasia; spondylometaphyseal.

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