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Am J Hum Genet. 2018 Oct 4;103(4):553-567. doi: 10.1016/j.ajhg.2018.09.003.

A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation.

Author information

1
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.
2
Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
3
Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA.
4
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
5
Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
6
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden.
7
Biochemical Genetics Laboratory, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
8
GeneDx, Gaithersburg, MD 20877, USA.
9
Genetic Unit, SARAH Network of Rehabilitation Hospitals, Brasília-DF, 70335-901, Brazil.
10
Department of Internal Medicine, Section of Paediatrics, Haugesund District Hospital, Fonna Health Trust, 5527 Haugesund, Norway.
11
Department of Medical Genetics, St. Olav's Hospital, 7006 Trondheim, Norway.
12
Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.
13
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.
14
Division of Orthogenetics, A.I. duPont Hospital for Children, Wilmington, DE, 19803, USA.
15
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.
16
Section of Rare Disorders, Department of Pediatrics, Rigshospitalet, 2100 Copenhagen, Denmark.
17
Department of Clinical Genetics, Rigshospitalet, 2100 Copenhagen, Denmark.
18
Ambry Genetics, Aliso Viejo, CA 92656, USA.
19
Division of Genetic Medicine, Seattle Children's, Seattle, WA, 98105, USA.
20
Division of Medical Genetics, Children's Hospital of Los Angeles, University of Southern California, Los Angeles, CA 90027, USA.
21
Division of Genetics, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton Ontario L8S 4J9, Canada.
22
Division of Medical genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
23
Department of Genetics, Kaiser Permanente, Los Angeles, CA 90027, USA.
24
Department of Pediatrics, University of Virginia Health System, Charlottesville, VA 20903, USA.
25
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.

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.

PMID:
30290151
PMCID:
PMC6174323
DOI:
10.1016/j.ajhg.2018.09.003
[Indexed for MEDLINE]
Free PMC Article

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