Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy

Hum Mutat. 2004 Feb;23(2):170-6. doi: 10.1002/humu.10306.

Abstract

Lafora disease is the most severe teenage-onset progressive epilepsy, a unique form of glycogenosis with perikaryal accumulation of an abnormal form of glycogen, and a neurodegenerative disorder exhibiting an unusual generalized organellar disintegration. The disease is caused by mutations of the EPM2A gene, which encodes two isoforms of the laforin protein tyrosine phosphatase, having alternate carboxyl termini, one localized in the cytoplasm (endoplasmic reticulum) and the other in the nucleus. To date, all documented disease mutations, including the knockout mouse model deletion, have been in the segment of the protein common to both isoforms. It is therefore not known whether dysfunction of the cytoplasmic, nuclear, or both isoforms leads to the disease. In the present work, we identify six novel mutations, one of which, c.950insT (Q319fs), is the first mutation specific to the cytoplasmic laforin isoform, implicating this isoform in disease pathogenesis. To confirm this mutation's deleterious effect on laforin, we studied the resultant protein's subcellular localization and function and show a drastic reduction in its phosphatase activity, despite maintenance of its location at the endoplasmic reticulum.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence / genetics
  • Animals
  • Base Sequence / genetics
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • Cytoplasm / chemistry*
  • Cytoplasm / genetics
  • Dual-Specificity Phosphatases
  • Endoplasmic Reticulum / chemistry
  • Endoplasmic Reticulum / genetics
  • Female
  • Humans
  • Lafora Disease / genetics*
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Mutation / genetics
  • Mutation, Missense / genetics
  • Pedigree
  • Protein Isoforms / deficiency
  • Protein Isoforms / genetics
  • Protein Isoforms / physiology
  • Protein Tyrosine Phosphatases / deficiency*
  • Protein Tyrosine Phosphatases / genetics*
  • Protein Tyrosine Phosphatases / physiology
  • Protein Tyrosine Phosphatases, Non-Receptor

Substances

  • Protein Isoforms
  • Dual-Specificity Phosphatases
  • Epm2a protein, mouse
  • Protein Tyrosine Phosphatases
  • Protein Tyrosine Phosphatases, Non-Receptor
  • EPM2A protein, human

Associated data

  • GENBANK/AY324850