title: Biochemical and ultrastructural evidence of endoplasmic reticulum stress in LGMD2I.
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 alpha-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 alpha-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 alpha-dystroglycan metabolism and malfunctioning.
authors.affiliation: Department of Neurosciences, University of Padova, via Giustiniani 5, 35128 Padova, Italy.
authors.forename: Chiara A
authors.initials: CA
authors.lastname: Boito
authors.forename: Marina
authors.initials: M
authors.lastname: Fanin
authors.forename: Bruno F
authors.initials: BF
authors.lastname: Gavassini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cenacchi
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.forename: Elena
authors.initials: E
authors.lastname: Pegoraro
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006031:Glycosylation; D006360:Heat-Shock Proteins / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D010430:Pentosyltransferases; D017510:Protein Folding; D011506:Proteins / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D018832:Molecular Chaperones; D011506:Proteins; D049030:Dystroglycans; D051742:Transcription Factor CHOP; C443107:FKRP protein, human; D010430:Pentosyltransferases