title: Abnormal distribution of calcium-handling proteins: a novel distinctive marker in core myopathies.
abstract: Central core disease (CCD) and multi-minicore disease (MmD) are muscle disorders characterized by foci of mitochondria depletion and sarcomere disorganization ("cores") in muscle fibers. Although core myopathies are the most frequent congenital myopathies, their pathogenesis remains elusive and specific diagnostic markers are lacking. Core myopathies are mostly caused by mutations in 2 sarcoplasmic reticulum proteins: the massive Ca-release channel RyR1 or the selenoprotein N (SelN) of unknown function. To search for distinctive markers and to obtain further pathophysiological insight, we identified the molecular defects in 12 core myopathy patients and analyzed the immunolocalization of 6 proteins of the Ca-release complex in their muscle biopsies. In 7 cases with RYR1 mutations (6 CCD, one MmD), RyR1 was depleted from the cores; in contrast, the other proteins of the sarcoplasmic reticulum (calsequestrin, SERCA1/2, and triadin) and the T-tubule (dihydropyridine receptor-alpha1subunit) accumulated within or around the lesions, suggesting an original modification of the Ca-release complex protein arrangement. Conversely, all Ca-related proteins were distributed normally in 5 MmD cases with SelN mutations. Our results provide an appropriate tool to orientate the differential and molecular diagnosis of core myopathies and suggest that different pathophysiological mechanisms lead to core formation in SelN- and in RyR1-related core myopathies.
authors.affiliation: Inserm U582, Institut de Myologie, Paris, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Herasse
authors.forename: Karine
authors.initials: K
authors.lastname: Parain
authors.forename: Isabelle
authors.initials: I
authors.lastname: Marty
authors.forename: Nicole
authors.initials: N
authors.lastname: Monnier
authors.forename: Angela M
authors.initials: AM
authors.lastname: Kaindl
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Leroy
authors.forename: Pascale
authors.initials: P
authors.lastname: Richard
authors.forename: Jöel
authors.initials: J
authors.lastname: Lunardi
authors.forename: Norma B
authors.initials: NB
authors.lastname: Romero
authors.forename: Ana
authors.initials: A
authors.lastname: Ferreiro
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D002155:Calsequestrin / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002648:Child; D004252:DNA Mutational Analysis; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008954:Models, Biological; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009135:Muscular Diseases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D020512:Myopathy, Central Core / Q000235:genetics / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D051140:Selenoproteins / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002155:Calsequestrin; D002352:Carrier Proteins; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C435489:SELENON protein, human; D051140:Selenoproteins; C070048:triadin