Polyglucosan myopathy and functional characterization of a novel <i>GYG1</i>
 mutation

Hedberg‐Oldfors, Carola; Mensch, Alexander; Visuttijai, Kittichate; Stoltenburg, G.; Stoevesandt, Dietrich; Kraya, Torsten; Oldfors, Anders; Zierz, Stephan

doi:10.1111/ane.12865

Cited by 17 publications

(12 citation statements)

References 17 publications

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“…However, data concerning the Gygl - null mouse model and patients with loss-of-function mutations in GYG1 (GSDXV, OMIM #613507) suggest that glycogenin 1 depletion leads to glycogen accumulation, cardiomyopathy and muscle weakness. Therefore, this protein might not be the best therapeutic target for Lafora disease 144–146 .…”

Section: The Road To New Therapiesmentioning

confidence: 99%

Lafora disease — from pathogenesis to treatment strategies

et al. 2018

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Lafora disease is a severe, autosomal recessive, progressive myoclonus epilepsy. The disease usually manifests in previously healthy adolescents, and death commonly occurs within 10 years of symptom onset. Lafora disease is caused by loss-of-function mutations in EPM2A or NHLRC1, which encode laforin and malin, respectively. The absence of either protein results in poorly branched, hyperphosphorylated glycogen, which precipitates, aggregates and accumulates into Lafora bodies. Evidence from Lafora disease genetic mouse models indicates that these intracellular inclusions are a principal driver of neurodegeneration and neurological disease. The integration of current knowledge on the function of laforin-malin as an interacting complex suggests that laforin recruits malin to parts of glycogen molecules where overly long glucose chains are forming, so as to counteract further chain extension. In the absence of either laforin or malin function, long glucose chains in specific glycogen molecules extrude water, form double helices and drive precipitation of those molecules, which over time accumulate into Lafora bodies. In this article, we review the genetic, clinical, pathological and molecular aspects of Lafora disease. We also discuss traditional antiseizure treatments for this condition, as well as exciting therapeutic advances based on the downregulation of brain glycogen synthesis and disease gene replacement.

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Section: The Road To New Therapiesmentioning

confidence: 99%

Lafora disease — from pathogenesis to treatment strategies

et al. 2018

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“…Moreover, we can also speculate that, like RACO-1, GN1 might be a substrate of TRIM7-mediated ubiquitination. However, because approximately 90% of GN1 is covalently bound to glycogen ( 50 ) and therefore not accessible to TRIM7, ubiquitination might have some relevance in the case of pathological mutants of the enzyme, which because of their inactivity are free of polysaccharide ( 51 , 52 , 53 , 54 ).…”

Section: Discussionmentioning

confidence: 99%

Crystal structure and mutational analysis of the human TRIM7 B30.2 domain provide insights into the molecular basis of its binding to glycogenin-1

Sosa

Issoglio

Carrizo

2021

Journal of Biological Chemistry

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“…The third group included cases with novel mutations that were classified as pathogenic based on the clinical findings including segregation analysis and on the biopsy results. GYG1 mutations cause AR GSD XV (33,54,61). The novel p.(Phe55*) and p.(Arg216*) GYG1 mutations in P13 each lead to premature termination of the coding sequence.…”

Section: Discussionmentioning

confidence: 99%

Differential diagnosis of vacuolar myopathies in the NGS era

et al. 2020

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Altered autophagy accompanied by abnormal autophagic (rimmed) vacuoles detectable by light and electron microscopy is a common denominator of many familial and sporadic non‐inflammatory muscle diseases. Even in the era of next generation sequencing (NGS), late‐onset vacuolar myopathies remain a diagnostic challenge. We identified 32 adult vacuolar myopathy patients from 30 unrelated families, studied their clinical, histopathological and ultrastructural characteristics and performed genetic testing in index patients and relatives using Sanger sequencing and NGS including whole exome sequencing (WES). We established a molecular genetic diagnosis in 17 patients. Pathogenic mutations were found in genes typically linked to vacuolar myopathy (GNE, LDB3/ZASP, MYOT, DES and GAA), but also in genes not regularly associated with severely altered autophagy (FKRP, DYSF, CAV3, COL6A2, GYG1 and TRIM32) and in the digenic facioscapulohumeral muscular dystrophy 2. Characteristic histopathological features including distinct patterns of myofibrillar disarray and evidence of exocytosis proved to be helpful to distinguish causes of vacuolar myopathies. Biopsy validated the pathogenicity of the novel mutations p.(Phe55*) and p.(Arg216*) in GYG1 and of the p.(Leu156Pro) TRIM32 mutation combined with compound heterozygous deletion of exon 2 of TRIM32 and expanded the phenotype of Ala93Thr‐caveolinopathy and of limb‐girdle muscular dystrophy 2i caused by FKRP mutation. In 15 patients no causal variants were detected by Sanger sequencing and NGS panel analysis. In 12 of these cases, WES was performed, but did not yield any definite mutation or likely candidate gene. In one of these patients with a family history of muscle weakness, the vacuolar myopathy was eventually linked to chloroquine therapy. Our study illustrates the wide phenotypic and genotypic heterogeneity of vacuolar myopathies and validates the role of histopathology in assessing the pathogenicity of novel mutations detected by NGS. In a sizable portion of vacuolar myopathy cases, it remains to be shown whether the cause is hereditary or degenerative.

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Polyglucosan myopathy and functional characterization of a novel GYG1 mutation

Abstract: We present functional evidence for the pathogenicity of a novel GYG1 missense mutation located in the substrate binding domain. Our results also demonstrate that glycogenin-1 deficiency may present with highly variable distribution of weakness and wasting also in the same family.

Cited by 17 publications

References 17 publications

Lafora disease — from pathogenesis to treatment strategies

Lafora disease — from pathogenesis to treatment strategies

Crystal structure and mutational analysis of the human TRIM7 B30.2 domain provide insights into the molecular basis of its binding to glycogenin-1

Differential diagnosis of vacuolar myopathies in the NGS era

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