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Biochemical and ultrastructural evidence of endoplasmic reticulum stress in LGMD2I

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Abstract

Limb girdle muscular dystrophy type 2I (LGMD2I) is due to mutations in the fukutin-related protein gene (FKRP), encoding a putative glycosyltransferase involved in α-dystroglycan processing. To further characterize the molecular pathogenesis of LGMD2I, we conducted a histological, immunohistochemical, ultrastructural and molecular analysis of ten muscle biopsies from patients with molecularly diagnosed LGMD2I. Hypoglycosylation of α-dystroglycan was observed in all FKRP-mutated patients. Muscle histopathology was consistent with either severe muscular dystrophy or myopathy with a mild inflammatory response consisting of up-regulation of class I major histocompatibility complex in skeletal muscle fibers and small foci of mononuclear cells. At the ultrastructural level, muscle fibers showed focal thinning of basal lamina and swollen endoplasmic reticulum cisternae with membrane re-arrangement. The pathways of the unfolded protein response (UPR; glucose-regulated protein 78 and CHOP) were significantly activated in LGMD2I muscle tissue. Our data suggest that the UPR response is activated in LGMD2I muscle biopsies, and the observed histopathological and ultrastructural alterations may be related to sarcoplasmic structures involved in FKRP and α-dystroglycan metabolism and malfunctioning.

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Acknowledgment

This study was supported by a grant from the Italian Telethon (number GTF05003) and EuroBioBank.

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Authors and Affiliations

  1. Department of Neurosciences, University of Padova, via Giustiniani 5, 35128, Padova, Italy

    Chiara A. Boito, Marina Fanin, Bruno F. Gavassini, Corrado Angelini & Elena Pegoraro

  2. Department of Pathology, University of Bologna, Bologna, Italy

    Giovanna Cenacchi

Authors
  1. Chiara A. Boito
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  2. Marina Fanin
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  3. Bruno F. Gavassini
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  4. Giovanna Cenacchi
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  5. Corrado Angelini
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  6. Elena Pegoraro
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Correspondence to Elena Pegoraro.

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Boito, C.A., Fanin, M., Gavassini, B.F. et al. Biochemical and ultrastructural evidence of endoplasmic reticulum stress in LGMD2I. Virchows Arch 451, 1047–1055 (2007). https://doi.org/10.1007/s00428-007-0515-3

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  • DOI: https://doi.org/10.1007/s00428-007-0515-3

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