title: Ca2+ dysregulation in Ryr1(I4895T/wt) mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods.
abstract: Ryr1(I4895T/wt) (IT/+) mice express a knockin mutation corresponding to the human I4898T EC-uncoupling mutation in the type 1 ryanodine receptor/Ca(2+) release channel (RyR1), which causes a severe form of central core disease (CCD). IT/+ mice exhibit a slowly progressive congenital myopathy, with neonatal respiratory stress, skeletal muscle weakness, impaired mobility, dorsal kyphosis, and hind limb paralysis. Lesions observed in myofibers from diseased mice undergo age-dependent transformation from minicores to cores and nemaline rods. Early ultrastructural abnormalities include sarcomeric misalignment, Z-line streaming, focal loss of cross-striations, and myofibrillar splitting and intermingling that may arise from defective myofibrillogenesis. However, manifestation of the disease phenotype is highly variable on a Sv129 genomic background. Quantitative RT-PCR shows an equimolar ratio of WT and mutant Ryr1 transcripts within IT/+ myofibers and total RyR1 protein expression levels are normal. We propose a unifying theory in which the cause of core formation lies in functional heterogeneity among RyR1 tetramers. Random combinations of normal and either leaky or EC-uncoupled RyR subunits would lead to spatial differences in Ca(2+) transients; the resulting heterogeneity of contraction among myofibrils would lead to focal, irreversible tearing and shearing, which would, over time, enlarge to form minicores, cores, and nemaline rods. The IT/+ mouse line is proposed to be a valid model of RyR1-related congenital myopathy, offering high potential for elucidation of the pathogenesis of skeletal muscle disorders arising from impaired EC coupling.
authors: Banting and Best Department of Medical Research, Charles H. Best Institute, University of Toronto, Toronto, Ontario, Canada M5G 1L6.
authors: Elena
authors: E
authors: Zvaritch
authors: Natasha
authors: N
authors: Kraeva
authors: Eric
authors: E
authors: Bombardier
authors: Robert A
authors: RA
authors: McCloy
authors: Frederic
authors: F
authors: Depreux
authors: Douglas
authors: D
authors: Holmyard
authors: Alexander
authors: A
authors: Kraev
authors: Christine E
authors: CE
authors: Seidman
authors: J G
authors: JG
authors: Seidman
authors: A Russell
authors: AR
authors: Tupling
authors: David H
authors: DH
authors: MacLennan
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D017696:Myopathies, Nemaline / Q000503:physiopathology*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium