Banting and Best Department of Medical Research, Charles H. Best Institute, University of Toronto, Toronto, Ontario, Canada M5G 1L6.
Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21813-8. doi: 10.1073/pnas.0912126106. Epub 2009 Dec 3.
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.
Ryr1(I4895T/wt) (IT/+) 小鼠表达了一种嵌合突变，对应于 1 型肌质网钙释放通道 (RyR1) 中的人类 I4898T EC 解偶联突变，这导致了一种严重的中央核心疾病 (CCD)。IT/+ 小鼠表现出一种缓慢进展的先天性肌病，伴有新生儿呼吸窘迫、骨骼肌无力、运动障碍、脊柱后凸和后肢瘫痪。从患病小鼠的肌纤维中观察到的病变经历了一个年龄依赖性的转变，从小核心到核心和杆状畸形。早期超微结构异常包括肌节排列不齐、Z 线流动、横纹带局灶性丧失以及肌原纤维分裂和混合，这可能是由于肌原纤维发生缺陷。然而，在 Sv129 基因组背景下，疾病表型的表现高度可变。定量 RT-PCR 显示 IT/+ 肌纤维中 WT 和突变型 Ryr1 转录本的比例相等，总 RyR1 蛋白表达水平正常。我们提出了一个统一的理论，即核心形成的原因在于 RyR1 四聚体之间的功能异质性。正常和渗漏或 EC 解偶联 RyR 亚基的随机组合将导致 Ca2+瞬变的空间差异；由此产生的肌原纤维收缩异质性将导致局灶性、不可逆的撕裂和剪切，随着时间的推移，这些撕裂和剪切会扩大形成小核心、核心和杆状畸形。IT/+ 小鼠品系被提议为 RyR1 相关先天性肌病的有效模型，为阐明由于 EC 偶联受损而导致的骨骼肌疾病的发病机制提供了很高的潜力。
