Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: Exon 1 mutations associate with an early-onset cognitive deficit subphenotype

Subramaniam Ganesh, Antonio V. Delgado-Escueta, Toshimitsu Suzuki, Silvana Francheschetti, Concetta Riggio, Giuiliano Avanzini, Adrian Rabinowicz, Saeed Bohlega, Julia Bailey, Maria E. Alonso, Astrid Rasmussen, Alfredo E. Thomson, Adria Na Ochoa, Aurelio J. Prado, Marco T. Medina, Kazuhiro Yamakawa

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause an autosomal recessive fatal disorder called Lafora's disease (LD) classically described as an adolescent-onset stimulus-sensitive myoclonus, epilepsy and neurologic deterioration. Here we related mutations in EPM2A with phenotypes of 22 patients (14 families) and identified two subsyndromes: (i) classical LD with adolescent-onset stimulus-sensitive grand mal, absence and myoclonic seizures followed by dementia and neurologic deterioration, and associated mainly with mutations in exon 4 (P=0.0007); (ii) atypical LD with childhood-onset dyslexia and learning disorder followed by epilepsy and neurologic deterioration, and associated mainly with mutations in exon 1 (P=0.0015). To understand the two subsyndromes better, we investigated the effect of five missense mutations in the carbohydrate-binding domain (CBD-4; coded by exon 1) and three missense mutations in the dual phosphatase domain (DSPD; coded by exons 3 and 4) on laforin's Intracellular localization in HeLa cells. Expression of three mutant proteins (T1941, G279S and Y294N) in DSPD formed ubiquitin-positive cytoplasmic aggregates, suggesting that they were folding mutants set for degradation. In contrast, none of the three CBD-4 mutants showed cytoplasmic clumping. However, CBD-4 mutants W32G and R108C targeted both cytoplasm and nucleus, suggesting that laforin had diminished its usual affinity for polysomes. Our data, thus, represent the first report of a novel childhood syndrome for LD. Our results also provide clues for distinct roles for the CBD-4 and DSP domains of laforin in the etiology of two subsyndromes of LD.

Original languageEnglish
Pages (from-to)1263-1271
Number of pages9
JournalHuman Molecular Genetics
Volume11
Issue number11
Publication statusPublished - May 15 2002

ASJC Scopus subject areas

  • Genetics

Fingerprint

Dive into the research topics of 'Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: Exon 1 mutations associate with an early-onset cognitive deficit subphenotype'. Together they form a unique fingerprint.

Cite this