Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype.
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.
Ganesh
Subramaniam
S
Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako-shi, Japan.
Delgado-Escueta
Antonio V
AV
Suzuki
Toshimitsu
T
Francheschetti
Silvana
S
Riggio
Concetta
C
Avanzini
Giuiliano
G
Rabinowicz
Adrian
A
Bohlega
Saeed
S
Bailey
Julia
J
Alonso
Maria E
ME
Rasmussen
Astrid
A
Thomson
Alfredo E
AE
Ochoa
Adriana
A
Prado
Aurelio J
AJ
Medina
Marco T
MT
Yamakawa
Kazuhiro
K
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
D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human