Fatal outcome due to deficiency of subunit 6 of the conserved oligomeric Golgi complex leading to a new type of congenital disorders of glycosylation

Research output: Contribution to journalArticle

Abstract

Deficiency of subunit 6 of the conserved oligomeric Golgi (COG6) complex causes a new combined N-and O-glycosylation deficiency of the congenital disorders of glycosylation, designated as CDG-IIL (COG6-CDG). The index patient presented with a severe neurologic disease characterized by vitamin K deficiency, vomiting, intractable focal seizures, intracranial bleedings and fatal outcome in early infancy. Analysis of oligosaccharides from serum transferrin by HPLC and mass spectrometry revealed the loss of galactose and sialic acid residues, whereas import and transfer of these sugar residues into Golgi-enriched vesicles or onto proteins, respectively, were normal to slightly reduced. Western blot examinations combined with gel filtration chromatography studies in patient-derived skin fibroblasts showed a severely reduced expression of the mentioned subunit and the occurrence of COG complex fragments at the expense of the integral COG complex. Sequencing of COG6-cDNA and COG6 gene resulted in a homozygous mutation (c.G1646T), leading to amino acid exchange p.G549V in the COG6 protein. Retroviral complementation of the patients' fibroblasts with the wild-type COG6-cDNA led to normalization of the COG complex-depending retrograde protein transport after Brefeldin A treatment, demonstrated by immunofluorescence analysis.

Details

Authors
  • Jürgen Lübbehusen
  • Christian Thiel
  • Nina Rind
  • Daniel Ungar
  • Berthil H.C.M.T. Prinsen
  • Tom J. de Koning
  • Peter M. van Hasselt
  • Christian Körner
External organisations
  • University Hospital Heidelberg
  • University of York
  • Wilhelmina Children’s Hospital
  • University Medical Center Utrecht
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Pages (from-to)3623-3633
JournalHuman Molecular Genetics
Volume19
Issue number18
Publication statusPublished - 2010 Sep 15
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes