title: Lafora progressive myoclonus epilepsy: NHLRC1 mutations affect glycogen metabolism.
abstract: Lafora disease is a fatal autosomal recessive form of progressive myoclonus epilepsy. Patients manifest myoclonus and tonic-clonic seizures, visual hallucinations, intellectual, and progressive neurologic deterioration beginning in adolescence. The two genes known to be involved in Lafora disease are EPM2A and NHLRC1 (EPM2B). The EPM2A gene encodes laforin, a dual-specificity protein phosphatase, and the NHLRC1 gene encodes malin, an E3-ubiquitin ligase. The two proteins interact with each other and, as a complex, are thought to regulate glycogen synthesis. Here, we report three Lafora families with two novel pathogenic mutations (C46Y and L261P) and two recurrent mutations (P69A and D146N) in NHLRC1. Investigation of their functional consequences in cultured mammalian cells revealed that malin(C46Y), malin(P69A), malin(D146N), and malin(L261P) mutants failed to downregulate the level of R5/PTG, a regulatory subunit of protein phosphatase 1 involved in glycogen synthesis. Abnormal accumulation of intracellular glycogen was observed with all malin mutants, reminiscent of the polyglucosan inclusions (Lafora bodies) present in patients with Lafora disease.
authors.affiliation: Inserm UMRS_975, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Couarch
authors.forename: Santiago
authors.initials: S
authors.lastname: Vernia
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gourfinkel-An
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Lesca
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gataullina
authors.forename: Estelle
authors.initials: E
authors.lastname: Fedirko
authors.forename: Oriane
authors.initials: O
authors.lastname: Trouillard
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.forename: Olivier
authors.initials: O
authors.lastname: Dulac
authors.forename: Dominique
authors.initials: D
authors.lastname: Steschenko
authors.forename: Eric
authors.initials: E
authors.lastname: Leguern
authors.forename: Pascual
authors.initials: P
authors.lastname: Sanz
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baulac
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006003:Glycogen / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D042541:Intracellular Space / Q000378:metabolism; D020192:Lafora Disease / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism; D016415:Sequence Alignment; D044767:Ubiquitin-Protein Ligases; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C491294:PPP1R3C protein, human; D006003:Glycogen; C478960:NHLRC1 protein, human; D044767:Ubiquitin-Protein Ligases; D010749:Phosphoprotein Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human