Article Text

PDF
Short Report
Hypothesis: lobe A (COG1–4)-CDG causes a more severe phenotype than lobe B (COG5–8)-CDG
  1. Hanneke A. Haijes1,
  2. Jaak Jaeken2,
  3. François Foulquier3,
  4. Peter M. van Hasselt4
  1. 1Department of Biomedical Genetics, Section Metabolic Diagnostics, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, Netherlands
  2. 2Department of Paediatrics, Centre for Metabolic Diseases, University Hospital Gasthuisberg, Leuven, Belgium
  3. 3Department of Structural and Functional Glycobiology, National Centre for Scientific Research, University of Lille, Lille, France
  4. 4Department of Paediatrics, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, Netherlands
  1. Correspondence to Hanneke A. Haijes, Wilhelmina Kinderziekenhuis, Lundlaan 6, 3584 EA Utrecht, Netherlands; h.a.siepel-3{at}umcutrecht.nl

Abstract

The conserved oligomeric Golgi (COG) complex consists of eight subunits organized in two lobes: lobe A (COG1–4) and lobe B (COG5–8). The different functional roles of COG lobe A and lobe B might result in distinct clinical phenotypes in patients with COG-CDG (congenital disorders of glycosylation). This hypothesis is supported by three observations. First, knock-down of COG lobe A components affects Golgi morphology more severely than knock-down of COG lobe B components. Second, nearly all of the 27 patients with lobe B COG-CDG had bi-allelic truncating mutations, as compared with only one of the six patients with lobe A COG-CDG. This represents a frequency gap which suggests that bi-allelic truncating mutations in COG lobe A genes might be non-viable. Third, in support, large-scale exome data of healthy adults (Exome Aggregation Consortium (ExAC)) underline that COG lobe A genes are less tolerant to genetic variation than COG lobe B genes. Thus, comparable molecular defects are more detrimental in lobe A COG-CDG than in lobe B COG-CDG. In a larger perspective, clinical phenotypic severity corresponded nicely with tolerance to genetic variation. Therefore, genomic epidemiology can potentially be used as a photographic negative for mutational severity.

  • COG
  • conserved oligomeric Golgi complex
  • CDG
  • congenital disorder(s) of glycosylation

Statistics from Altmetric.com

Footnotes

  • Contributors HAH conceptualised and designed the study, collected the data, drafted the initial manuscript and approved the final manuscript as submitted. JJ and FF critically reviewed the initial manuscript and approved the final manuscript as submitted. PMvH conceptualised and supervised the design and data collection of the study, critically reviewed the initial manuscript and approved the final manuscript as submitted.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All data are available on request.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.