A PTG variant contributes to a milder phenotype in Lafora disease.
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 d...
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2011
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oai:doaj.org-article:decbd37294894b3a9ad223c460a37b7c2021-11-18T06:50:55ZA PTG variant contributes to a milder phenotype in Lafora disease.1932-620310.1371/journal.pone.0021294https://doaj.org/article/decbd37294894b3a9ad223c460a37b7c2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21738631/?tool=EBIhttps://doaj.org/toc/1932-6203Lafora 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.Rosa GuerreroSantiago VerniaRaúl SanzIrene Abreu-RodríguezCarmen AlmarazMaría García-HoyosRoberto MichelucciCarlo Alberto TassinariPatrizia RiguzziCarlo NobilePascual SanzJosé M SerratosaPilar Gómez-GarrePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 6, p e21294 (2011) |
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Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Rosa Guerrero Santiago Vernia Raúl Sanz Irene Abreu-Rodríguez Carmen Almaraz María García-Hoyos Roberto Michelucci Carlo Alberto Tassinari Patrizia Riguzzi Carlo Nobile Pascual Sanz José M Serratosa Pilar Gómez-Garre A PTG variant contributes to a milder phenotype in Lafora disease. |
| description |
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. |
| format |
article |
| author |
Rosa Guerrero Santiago Vernia Raúl Sanz Irene Abreu-Rodríguez Carmen Almaraz María García-Hoyos Roberto Michelucci Carlo Alberto Tassinari Patrizia Riguzzi Carlo Nobile Pascual Sanz José M Serratosa Pilar Gómez-Garre |
| author_facet |
Rosa Guerrero Santiago Vernia Raúl Sanz Irene Abreu-Rodríguez Carmen Almaraz María García-Hoyos Roberto Michelucci Carlo Alberto Tassinari Patrizia Riguzzi Carlo Nobile Pascual Sanz José M Serratosa Pilar Gómez-Garre |
| author_sort |
Rosa Guerrero |
| title |
A PTG variant contributes to a milder phenotype in Lafora disease. |
| title_short |
A PTG variant contributes to a milder phenotype in Lafora disease. |
| title_full |
A PTG variant contributes to a milder phenotype in Lafora disease. |
| title_fullStr |
A PTG variant contributes to a milder phenotype in Lafora disease. |
| title_full_unstemmed |
A PTG variant contributes to a milder phenotype in Lafora disease. |
| title_sort |
ptg variant contributes to a milder phenotype in lafora disease. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/decbd37294894b3a9ad223c460a37b7c |
| work_keys_str_mv |
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