title: Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype.
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 (T194I, 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.
authors.affiliation: Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako-shi, Japan.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ganesh
authors.forename: Antonio V
authors.initials: AV
authors.lastname: Delgado-Escueta
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Silvana
authors.initials: S
authors.lastname: Francheschetti
authors.forename: Concetta
authors.initials: C
authors.lastname: Riggio
authors.forename: Giuiliano
authors.initials: G
authors.lastname: Avanzini
authors.forename: Adrian
authors.initials: A
authors.lastname: Rabinowicz
authors.forename: Saeed
authors.initials: S
authors.lastname: Bohlega
authors.forename: Julia
authors.initials: J
authors.lastname: Bailey
authors.forename: Maria E
authors.initials: ME
authors.lastname: Alonso
authors.forename: Astrid
authors.initials: A
authors.lastname: Rasmussen
authors.forename: Alfredo E
authors.initials: AE
authors.lastname: Thomson
authors.forename: Adriana
authors.initials: A
authors.lastname: Ochoa
authors.forename: Aurelio J
authors.initials: AJ
authors.lastname: Prado
authors.forename: Marco T
authors.initials: MT
authors.lastname: Medina
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamakawa
mesh_terms: D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006239:Haplotypes; D006367:HeLa Cells; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D020192:Lafora Disease / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics*; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D017422:Sequence Analysis, DNA
chemical_list: D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human