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- Oldfors Hedberg, Carola, 1969, et al.
(författare)
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Polyglucosan myopathy and functional characterization of a novel GYG1 mutation
- 2018
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314. ; 137:3, s. 308-315
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Disorders of glycogen metabolism include rare hereditary muscle glycogen storage diseases with polyglucosan, which are characterized by storage of abnormally structured glycogen in muscle in addition to exercise intolerance or muscle weakness. In this study, we investigated the etiology and pathogenesis of a late-onset myopathy associated with glycogenin-1 deficiency. Materials and methods: A family with two affected siblings, 64- and 66-year-olds, was studied. Clinical examination and whole-body MRI revealed weakness and wasting in the hip girdle and proximal leg muscles affecting ambulation in the brother. The sister had weakness and atrophy of hands and slight foot dorsiflexion difficulties. Muscle biopsy and whole-exome sequencing were performed in both cases to identify and characterize the pathogenesis including the functional effects of identified mutations. Results: Both siblings demonstrated storage of glycogen that was partly resistant to alpha-amylase digestion. Both were heterozygous for two mutations in GYG1, one truncating 1-base deletion (c.484delG; p.Asp163Thrfs*5) and one novel missense mutation (c.403G>A; p.Gly135Arg). The mutations caused reduced expression of glycogenin-1 protein, and the missense mutation abolished the enzymatic function as analyzed by an in vitro autoglucosylation assay. Conclusion: 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.
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- Pendrill, Robert, et al.
(författare)
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Solution Structure of Mannobioses Unravelled by Means of Raman Optical Activity
- 2019
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Ingår i: ChemPhysChem. - : Wiley. - 1439-4235 .- 1439-7641. ; 20:5, s. 695-705
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Tidskriftsartikel (refereegranskat)abstract
- Structural analysis of carbohydrates is a complicated endeavour, due to the complexity and diversity of the samples at hand. Herein, we apply a combined computational and experimental approach, employing molecular dynamics (MD) and density functional theory (DFT) calculations together with NMR and Raman optical activity (ROA) measurements, in the structural study of three mannobiose disaccharides, consisting of two mannoses with varying glycosidic linkages. The disaccharide structures make up the scaffold of high mannose glycans and are therefore important targets for structural analysis. Based on the MD population analysis and NMR, the major conformers of each mannobiose were identified and used as input for DFT analysis. By systematically varying the solvent models used to describe water interacting with the molecules and applying overlap integral analysis to the resulting calculational ROA spectra, we found that a full quantum mechanical/molecular mechanical approach is required for an optimal calculation of the ROA parameters. Subsequent normal mode analysis of the predicted vibrational modes was attempted in order to identify possible marker bands for glycosidic linkages. However, the normal mode vibrations of the mannobioses are completely delocalised, presumably due to conformational flexibility in these compounds, rendering the identification of isolated marker bands unfeasible.
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