PDF(Pubmed)
Abstract：
Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by childhood-onset muscle weakness and a variable occurrence of multisystemic signs, including short stature, thrombocytopenia, and hyposplenism. TAM/STRMK is caused by gain-of-function mutations in the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1, both of which regulate Ca2+ homeostasis through the ubiquitous store-operated Ca2+ entry (SOCE) mechanism. Functional experiments in cells have demonstrated that the TAM/STRMK mutations induce SOCE overactivation, resulting in excessive influx of extracellular Ca2+. There is currently no treatment for TAM/STRMK, but SOCE is amenable to manipulation. Here, we crossed Stim1R304W/+ mice harboring the most common TAM/STRMK mutation with Orai1R93W/+ mice carrying an ORAI1 mutation partially obstructing Ca2+ influx. Compared with Stim1R304W/+ littermates, Stim1R304W/+Orai1R93W/+ offspring showed a normalization of bone architecture, spleen histology, and muscle morphology; an increase of thrombocytes; and improved muscle contraction and relaxation kinetics. Accordingly, comparative RNA-Seq detected more than 1,200 dysregulated genes in Stim1R304W/+ muscle and revealed a major restoration of gene expression in Stim1R304W/+Orai1R93W/+ mice. Altogether, we provide physiological, morphological, functional, and molecular data highlighting the therapeutic potential of ORAI1 inhibition to rescue the multisystemic TAM/STRMK signs, and we identified myostatin as a promising biomarker for TAM/STRMK in humans and mice.
摘要：
肾小管聚集肌病（TAM）和Stormorken综合征（STRMK）是临床上重叠的疾病，其特征是儿童期起病的肌无力和多系统体征的可变发生。包括身材矮小，血小板减少症,和脾功能减退.TAM/STRMK是由Ca2传感器STIM1或Ca2通道ORAI1中的功能获得突变引起的，两者都通过普遍存在的存储操作的Ca2进入（SOCE）机制来调节Ca2稳态。细胞中的功能实验表明，TAM/STRMK突变诱导SOCE过度激活，导致细胞外Ca2+过度流入。目前没有TAM/STRMK的治疗方法,但是SOCE适合操纵。这里,我们将携带最常见TAM/STRMK突变的Stim1R304W/+小鼠与携带ORAI1突变的Orai1R93W/+小鼠交叉,部分阻碍Ca2+流入.与Stim1R304W/+同窝相比，Stim1R304W/+Orai1R93W/+后代显示骨骼结构正常化，脾脏组织学,和肌肉形态；血小板增加；并改善肌肉收缩和松弛动力学。因此，比较RNA-Seq在Stim1R304W/肌肉中检测到超过1,200个失调基因，并揭示了Stim1R304W/Orai1R93W/小鼠中基因表达的主要恢复。总之,我们提供生理，形态学,功能，和分子数据突出ORAI1抑制挽救多系统TAM/STRMK体征的治疗潜力，我们确定肌肉生长抑制素是人类和小鼠TAM/STRMK的有希望的生物标志物。
