Golgi function and dysfunction in the first COG4-deficient CDG type II patient

Hum Mol Genet. 2009 Sep 1;18(17):3244-56. doi: 10.1093/hmg/ddp262. Epub 2009 Jun 3.

Abstract

The conserved oligomeric Golgi (COG) complex is a hetero-octameric complex essential for normal glycosylation and intra-Golgi transport. An increasing number of congenital disorder of glycosylation type II (CDG-II) mutations are found in COG subunits indicating its importance in glycosylation. We report a new CDG-II patient harbouring a p.R729W missense mutation in COG4 combined with a submicroscopical deletion. The resulting downregulation of COG4 expression additionally affects expression or stability of other lobe A subunits. Despite this, full complex formation was maintained albeit to a lower extent as shown by glycerol gradient centrifugation. Moreover, our data indicate that subunits are present in a cytosolic pool and full complex formation assists tethering preceding membrane fusion. By extending this study to four other known COG-deficient patients, we now present the first comparative analysis on defects in transport, glycosylation and Golgi ultrastructure in these patients. The observed structural and biochemical abnormalities correlate with the severity of the mutation, with the COG4 mutant being the mildest. All together our results indicate that intact COG complexes are required to maintain Golgi dynamics and its associated functions. According to the current CDG nomenclature, this newly identified deficiency is designated CDG-IIj.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Carbohydrate Metabolism, Inborn Errors / genetics
  • Carbohydrate Metabolism, Inborn Errors / metabolism*
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Child, Preschool
  • Female
  • Fibroblasts / metabolism
  • Glycosylation
  • Golgi Apparatus / chemistry
  • Golgi Apparatus / genetics
  • Golgi Apparatus / metabolism*
  • HeLa Cells
  • Humans
  • Infant
  • Male
  • Molecular Sequence Data
  • Protein Transport
  • Sequence Homology, Amino Acid
  • Vesicular Transport Proteins

Substances

  • COG4 protein, human
  • Carrier Proteins
  • Vesicular Transport Proteins