Laforin targets malin to glycogen in Lafora progressive myoclonus epilepsy

Sharmistha Mitra, Baozhi Chen, Peixiang Wang, Erin E. Chown, Mathew Dear, Dikran R. Guisso, Ummay Mariam, Jun Wu, Emrah Gumusgoz, Berge A. Minassian

Research output: Contribution to journalArticlepeer-review


Glycogen is the largest cytosolic macromolecule and is kept in solution through a regular system of short branches allowing hydration. This structure was thought to solely require balanced glycogen synthase and branching enzyme activities. Deposition of overlong branched glycogen in the fatal epilepsy Lafora disease (LD) indicated involvement of the LD gene products laforin and the E3 ubiquitin ligase malin in regulating glycogen structure. Laforin binds glycogen, and LD-causing mutations disrupt this binding, laforin-malin interactions and malin's ligase activity, all indicating a critical role for malin. Neither malin's endogenous function nor location had previously been studied due to lack of suitable antibodies. Here, we generated a mouse in which the native malin gene is tagged with the FLAG sequence. We show that the tagged gene expresses physiologically, malin localizes to glycogen, laforin and malin indeed interact, at glycogen, and malin's presence at glycogen depends on laforin. These results, and mice, open the way to understanding unknown mechanisms of glycogen synthesis critical to LD and potentially other much more common diseases due to incompletely understood defects in glycogen metabolism.

Original languageEnglish (US)
JournalDisease models & mechanisms
Issue number1
StatePublished - Jan 1 2023


  • Lafora body
  • Myoclonus
  • Polyglucosan

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)


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