PUBLICATION

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

Authors
Ferreira, C.R., Xia, Z.J., Clément, A., Parry, D.A., Davids, M., Taylan, F., Sharma, P., Turgeon, C.T., Blanco-Sánchez, B., Ng, B.G., Logan, C.V., Wolfe, L.A., Solomon, B.D., Cho, M.T., Douglas, G., Carvalho, D.R., Bratke, H., Haug, M.G., Phillips, J.B., Wegner, J., Tiemeyer, M., Aoki, K., Undiagnosed Diseases Network, Scottish Genome Partnership, Nordgren, A., Hammarsjö, A., Duker, A.L., Rohena, L., Hove, H.B., Ek, J., Adams, D., Tifft, C.J., Onyekweli, T., Weixel, T., Macnamara, E., Radtke, K., Powis, Z., Earl, D., Gabriel, M., Russi, A.H.S., Brick, L., Kozenko, M., Tham, E., Raymond, K.M., Phillips, J.A., Tiller, G.E., Wilson, W.G., Hamid, R., Malicdan, M.C.V., Nishimura, G., Grigelioniene, G., Jackson, A., Westerfield, M., Bober, M.B., Gahl, W.A., Freeze, H.H.
ID
ZDB-PUB-190515-5
Date
2018
Source
American journal of human genetics   103: 553-567 (Journal)
Registered Authors
Blanco, Bernardo, Clément, Aurélie, Phillips, Jennifer, Wegner, Jeremy, Westerfield, Monte
Keywords
none
MeSH Terms
  • Adult
  • Amino Acid Substitution/genetics
  • Animals
  • Animals, Genetically Modified/genetics
  • Cell Line
  • Child
  • Child, Preschool
  • Endoplasmic Reticulum/genetics
  • Extracellular Matrix/genetics
  • Female
  • Fibroblasts/pathology
  • Fragile X Syndrome/genetics*
  • Glycosylation
  • Golgi Apparatus/genetics
  • Heterozygote
  • Humans
  • Infant
  • Male
  • Protein Transport/genetics*
  • Proteoglycans/genetics*
  • Vesicular Transport Proteins/genetics*
  • Zebrafish
PubMed
30290151 Full text @ Am. J. Hum. Genet.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes