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Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy
Author(s) -
Ianzano Leonarda,
Young Edwin J.,
Zhao Xiao C.,
Chan Elayne M.,
Rodriguez M. T.,
Torrado Maria V.,
Scherer Stephen W.,
Minassian Berge A.
Publication year - 2004
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.10306
Subject(s) - lafora disease , progressive myoclonus epilepsy , endoplasmic reticulum , biology , gene isoform , cytoplasm , unfolded protein response , mutation , protein tyrosine phosphatase , microbiology and biotechnology , neurodegeneration , genetics , gene , phosphatase , medicine , disease , signal transduction , phosphorylation
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. Hum Mutat 23:170–176, 2004. © 2003 Wiley‐Liss, Inc.