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A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation.
Ferreira, Carlos R; Xia, Zhi-Jie; Clément, Aurélie; Parry, David A; Davids, Mariska; Taylan, Fulya; Sharma, Prashant; Turgeon, Coleman T; Blanco-Sánchez, Bernardo; Ng, Bobby G; Logan, Clare V; Wolfe, Lynne A; Solomon, Benjamin D; Cho, Megan T; Douglas, Ganka; Carvalho, Daniel R; Bratke, Heiko; Haug, Marte Gjøl; Phillips, Jennifer B; Wegner, Jeremy; Tiemeyer, Michael; Aoki, Kazuhiro; Nordgren, Ann; Hammarsjö, Anna; Duker, Angela L; Rohena, Luis; Hove, Hanne Buciek; Ek, Jakob; Adams, David; Tifft, Cynthia J; Onyekweli, Tito; Weixel, Tara; Macnamara, Ellen; Radtke, Kelly; Powis, Zöe; Earl, Dawn; Gabriel, Melissa; Russi, Alvaro H Serrano; Brick, Lauren; Kozenko, Mariya; Tham, Emma; Raymond, Kimiyo M; Phillips, John A; Tiller, George E; Wilson, William G; Hamid, Rizwan; Malicdan, May C V; Nishimura, Gen; Grigelioniene, Giedre; Jackson, Andrew.
Affiliation
  • Ferreira CR; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; Division of Genetics and Metabolism, Children's National Health System, Washington, DC 20010, USA. Electronic address: carlos.ferreira@nih.gov.
  • Xia ZJ; Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • Clément A; Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA.
  • Parry DA; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • Davids M; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Taylan F; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Sharma P; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Turgeon CT; Biochemical Genetics Laboratory, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • Blanco-Sánchez B; Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA.
  • Ng BG; Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • Logan CV; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • Wolfe LA; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Solomon BD; GeneDx, Gaithersburg, MD 20877, USA.
  • Cho MT; GeneDx, Gaithersburg, MD 20877, USA.
  • Douglas G; GeneDx, Gaithersburg, MD 20877, USA.
  • Carvalho DR; Genetic Unit, SARAH Network of Rehabilitation Hospitals, Brasília-DF, 70335-901, Brazil.
  • Bratke H; Department of Internal Medicine, Section of Paediatrics, Haugesund District Hospital, Fonna Health Trust, 5527 Haugesund, Norway.
  • Haug MG; Department of Medical Genetics, St. Olav's Hospital, 7006 Trondheim, Norway.
  • Phillips JB; Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA.
  • Wegner J; Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA.
  • Tiemeyer M; Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.
  • Aoki K; Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.
  • Nordgren A; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
  • Hammarsjö A; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
  • Duker AL; Division of Orthogenetics, A.I. duPont Hospital for Children, Wilmington, DE, 19803, USA.
  • Rohena L; Division of Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, TX, 78234, USA; Department of Pediatrics, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
  • Hove HB; Section of Rare Disorders, Department of Pediatrics, Rigshospitalet, 2100 Copenhagen, Denmark.
  • Ek J; Department of Clinical Genetics, Rigshospitalet, 2100 Copenhagen, Denmark.
  • Adams D; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Tifft CJ; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Onyekweli T; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Weixel T; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Macnamara E; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Radtke K; Ambry Genetics, Aliso Viejo, CA 92656, USA.
  • Powis Z; Ambry Genetics, Aliso Viejo, CA 92656, USA.
  • Earl D; Division of Genetic Medicine, Seattle Children's, Seattle, WA, 98105, USA.
  • Gabriel M; Division of Medical Genetics, Children's Hospital of Los Angeles, University of Southern California, Los Angeles, CA 90027, USA.
  • Russi AHS; Division of Medical Genetics, Children's Hospital of Los Angeles, University of Southern California, Los Angeles, CA 90027, USA.
  • Brick L; Division of Genetics, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton Ontario L8S 4J9, Canada.
  • Kozenko M; Division of Genetics, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton Ontario L8S 4J9, Canada.
  • Tham E; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
  • Raymond KM; Biochemical Genetics Laboratory, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • Phillips JA; Division of Medical genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
  • Tiller GE; Department of Genetics, Kaiser Permanente, Los Angeles, CA 90027, USA.
  • Wilson WG; Department of Pediatrics, University of Virginia Health System, Charlottesville, VA 20903, USA.
  • Hamid R; Division of Medical genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
  • Malicdan MCV; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Nishimura G; Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan; Center for Intractable Diseases, Saitama Medical University Hospital, Saitama 350-0495, Japan.
  • Grigelioniene G; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
  • Jackson A; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Am J Hum Genet ; 103(4): 553-567, 2018 10 04.
Article in En | MEDLINE | ID: mdl-30290151
ABSTRACT
The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Proteoglycans / Protein Transport / Vesicular Transport Proteins / Fragile X Syndrome Limits: Adult / Animals / Child / Child, preschool / Female / Humans / Infant / Male Language: En Journal: Am J Hum Genet Year: 2018 Type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Proteoglycans / Protein Transport / Vesicular Transport Proteins / Fragile X Syndrome Limits: Adult / Animals / Child / Child, preschool / Female / Humans / Infant / Male Language: En Journal: Am J Hum Genet Year: 2018 Type: Article