title: Autophagic vacuolar pathology in desminopathies.
abstract: Autophagic vacuolar myopathies are an emerging group of muscle diseases with common pathologic features. These include autophagic vacuoles containing both lysosomal and autophagosomal proteins sometimes lined with sarcolemmal proteins such as dystrophin. These features have been most clearly described in patients with Danon's disease due to LAMP2 deficiency and X-linked myopathy with excessive autophagy (XMEA) due to mutations in VMA21. Disruptions of these proteins lead to lysosomal dysfunction and subsequent autophagic vacuolar pathology. We performed whole exome sequencing on two families with autosomal dominantly inherited myopathies with autophagic vacuolar pathology and surprisingly identified a p.R454W tail domain mutation and a novel p.S6W head domain mutation in desmin, DES. In addition, re-evaluation of muscle tissue from another family with a novel p.I402N missense DES mutation also identified autophagic vacuoles. We suggest that autophagic vacuoles may be an underappreciated pathology present in desminopathy patient muscle. Moreover, autophagic vacuolar pathology can be due to genetic etiologies unrelated to primary defects in the lysosomes or autophagic machinery. Specifically, cytoskeletal derangement and the accumulation of aggregated proteins such as desmin may activate the autophagic system leading to the pathologic features of an autophagic vacuolar myopathy.
authors.affiliation: Department of Neurology and Hope Center for Neurologic Disorders, Washington University School of Medicine, Saint Louis, MO, USA. Electronic address: weihlc@neuro.wustl.edu.
authors.forename: Conrad C
authors.initials: CC
authors.lastname: Weihl
authors.affiliation: Department of Neurology, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Iyadurai
authors.affiliation: Department of Neurology, Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Baloh
authors.affiliation: Department of Neurology and Hope Center for Neurologic Disorders, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Sara K
authors.initials: SK
authors.lastname: Pittman
authors.affiliation: Department of Pathology, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schmidt
authors.affiliation: Department of Neurology and Hope Center for Neurologic Disorders, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Lopate
authors.affiliation: Department of Neurology and Hope Center for Neurologic Disorders, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.affiliation: Department of Neurology and Hope Center for Neurologic Disorders, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Harms
mesh_terms: D000328:Adult; D000368:Aged; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D003893:Desmin / Q000235:genetics*; D005190:Family; D005260:Female; D006225:Hand / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D016464:Lysosomal Storage Diseases / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: D003893:Desmin
keywords: Autophagy; Desmin; Myofibrillar myopathy; Protein aggregation