Molecular pathogenesis of a new glycogenosis caused by a glycogenin-1 mutation

Biochim Biophys Acta. 2012 Apr;1822(4):493-9. doi: 10.1016/j.bbadis.2011.11.017. Epub 2011 Dec 9.


Glycogenin-1 initiates the glycogen synthesis in skeletal muscle by the autocatalytic formation of a short oligosaccharide at tyrosine 195. Glycogenin-1 catalyzes both the glucose-O-tyrosine linkage and the α1,4 glucosidic bonds linking the glucose molecules in the oligosaccharide. We recently described a patient with glycogen depletion in skeletal muscle as a result of a non-functional glycogenin-1. The patient carried a Thr83Met substitution in glycogenin-1. In this study we have investigated the importance of threonine 83 for the catalytic activity of glycogenin-1. Non-glucosylated glycogenin-1 constructs, with various amino acid substitutions in position 83 and 195, were expressed in a cell-free expression system and autoglucosylated in vitro. The autoglucosylation was analyzed by gel-shift on western blot, incorporation of radiolabeled UDP-(14)C-glucose and nano-liquid chromatography with tandem mass spectrometry (LC/MS/MS). We demonstrate that glycogenin-1 with the Thr83Met substitution is unable to form the glucose-O-tyrosine linkage at tyrosine 195 unless co-expressed with the catalytically active Tyr195Phe glycogenin-1. Our results explain the glycogen depletion in the patient expressing only Thr83Met glycogenin-1 and why heterozygous carriers without clinical symptoms show a small proportion of unglucosylated glycogenin-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Biocatalysis
  • Cell-Free System
  • Chromatography, Gel
  • Chromatography, Liquid
  • DNA Primers
  • Glucose / metabolism
  • Glucosyltransferases / chemistry
  • Glucosyltransferases / genetics*
  • Glucosyltransferases / isolation & purification
  • Glycogen / biosynthesis*
  • Glycoproteins / chemistry
  • Glycoproteins / genetics*
  • Glycoproteins / isolation & purification
  • Humans
  • Molecular Sequence Data
  • Mutation*
  • Tandem Mass Spectrometry


  • DNA Primers
  • Glycoproteins
  • glycogenin
  • Glycogen
  • Glucosyltransferases
  • Glucose