Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 103, Issue 4, Pages 553-567Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2018.09.003
Keywords
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Categories
Funding
- NHGRI
- NIH [U54 NS093793, R01 DK99551, HD22486, R21 AI129873]
- Rocket Fund
- Stockholm County Council
- Karolinska Institutet, KID
- Kronprinsessan Lovisas and Axel Tiellmans Minnesfond
- Barncancerfonden
- Hjarnfonden
- Samariten Foundation
- Sallskapet Barnavard Foundation
- Promobilia Foundation
- Stiftelsen Frimurare Barnhuset i Stockholm
- ERC [281847]
- Medical Research Council Human Genetics Unit core grant (MRC) [U127580972]
- Scottish Genomes Partnership
- Chief Scientist Office of the Scottish Government Health Directorates [SGP/1]
- Medical Research Council Whole Genome Sequencing for Health and Wealth Initiative
- Potentials Foundation
- Walking With Giants Foundation
- NIH-NIGMS [P41 GM103490]
- [HHSN268201700060P]
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [P01HD022486] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [ZIAHG200402, ZIAHG000215] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R21AI129873] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK099551] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P41GM103490] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [U54NS093793] Funding Source: NIH RePORTER
- MRC [MC_PC_U127580972] Funding Source: UKRI
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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 (COGS-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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