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

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  • Carlos R Ferreira
  • Zhi-Jie Xia
  • Aurélie Clément
  • David A Parry
  • Mariska Davids
  • Fulya Taylan
  • Prashant Sharma
  • Coleman T Turgeon
  • Bernardo Blanco-Sánchez
  • Bobby G Ng
  • Clare V Logan
  • Lynne A Wolfe
  • Benjamin D Solomon
  • Megan T Cho
  • Ganka Douglas
  • Daniel R Carvalho
  • Heiko Bratke
  • Marte Gjøl Haug
  • Jennifer B Phillips
  • Jeremy Wegner
  • Michael Tiemeyer
  • Kazuhiro Aoki
  • Ann Nordgren
  • Anna Hammarsjö
  • Angela L Duker
  • Luis Rohena
  • Hanne Buciek Hove
  • Jakob Ek
  • David Adams
  • Cynthia J Tifft
  • Tito Onyekweli
  • Tara Weixel
  • Ellen Macnamara
  • Kelly Radtke
  • Zöe Powis
  • Dawn Earl
  • Melissa Gabriel
  • Alvaro H Serrano Russi
  • Lauren Brick
  • Mariya Kozenko
  • Emma Tham
  • Kimiyo M Raymond
  • John A Phillips
  • George E Tiller
  • William G Wilson
  • Rizwan Hamid
  • May C V Malicdan
  • Gen Nishimura
  • Giedre Grigelioniene
  • Andrew Jackson
  • Undiagnosed Diseases Network
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftAmerican Journal of Human Genetics
Vol/bind103
Udgave nummer4
Sider (fra-til)553-567
Antal sider15
ISSN0002-9297
DOI
StatusUdgivet - 4 okt. 2018

ID: 56073658