title: A PTG variant contributes to a milder phenotype in Lafora disease.
abstract: Lafora disease is an autosomal recessive form of progressive myoclonus epilepsy with no effective therapy. Although the outcome is always unfavorable, onset of symptoms and progression of the disease may vary. We aimed to identify modifier genes that may contribute to the clinical course of Lafora disease patients with EPM2A or EPM2B mutations. We established a list of 43 genes coding for proteins related to laforin/malin function and/or glycogen metabolism and tested common polymorphisms for possible associations with phenotypic differences using a collection of Lafora disease families. Genotype and haplotype analysis showed that PPP1R3C may be associated with a slow progression of the disease. The PPP1R3C gene encodes protein targeting to glycogen (PTG). Glycogen targeting subunits play a major role in recruiting type 1 protein phosphatase (PP1) to glycogen-enriched cell compartments and in increasing the specific activity of PP1 toward specific glycogenic substrates (glycogen synthase and glycogen phosphorylase). Here, we report a new mutation (c.746A>G, N249S) in the PPP1R3C gene that results in a decreased capacity to induce glycogen synthesis and a reduced interaction with glycogen phosphorylase and laforin, supporting a key role of this mutation in the glycogenic activity of PTG. This variant was found in one of two affected siblings of a Lafora disease family characterized by a remarkable mild course. Our findings suggest that variations in PTG may condition the course of Lafora disease and establish PTG as a potential target for pharmacogenetic and therapeutic approaches.
authors: Laboratorio de Neurología-Unidad de Epilepsia, Servicio de Neurología, Instituto Investigación Sanitaria Fundación Jiménez Díaz, and Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
authors: Rosa
authors: R
authors: Guerrero
authors: Santiago
authors: S
authors: Vernia
authors: Raúl
authors: R
authors: Sanz
authors: Irene
authors: I
authors: Abreu-Rodríguez
authors: Carmen
authors: C
authors: Almaraz
authors: María
authors: M
authors: García-Hoyos
authors: Roberto
authors: R
authors: Michelucci
authors: Carlo Alberto
authors: CA
authors: Tassinari
authors: Patrizia
authors: P
authors: Riguzzi
authors: Carlo
authors: C
authors: Nobile
authors: Pascual
authors: P
authors: Sanz
authors: José M
authors: JM
authors: Serratosa
authors: Pilar
authors: P
authors: Gómez-Garre
mesh_terms: D000328:Adult; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005838:Genotype; D057809:HEK293 Cells; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020192:Lafora Disease / Q000235:genetics* / Q000473:pathology; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D020798:Two-Hybrid System Techniques; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C491294:PPP1R3C protein, human; D034741:RNA, Small Interfering; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1