Abnormal distribution of calcium-handling proteins: a novel distinctive marker in core myopathies.
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.
Herasse
Muriel
M
Inserm U582, Institut de Myologie, Paris, France.
Parain
Karine
K
Marty
Isabelle
I
Monnier
Nicole
N
Kaindl
Angela M
AM
Leroy
Jean-Paul
JP
Richard
Pascale
P
Lunardi
Jöel
J
Romero
Norma B
NB
Ferreiro
Ana
A
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
D015415:Biomarkers; D002155:Calsequestrin; D002352:Carrier Proteins; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C435489:SELENON protein, human; D051140:Selenoproteins; C070048:triadin