An RYR1 mutation associated with malignant hyperthermia is also associated with bleeding abnormalities
An RYR1 mutation associated with malignant hyperthermia is also associated with bleeding abnormalities
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DOI：
10.1126/scisignal.aad9813
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发表时间：
2016-07-05
影响因子：
7.3
通讯作者：
Jungbluth, Heinz
中科院分区：
文献类型：
--
作者：
Lopez, Ruben J.;Byrne, Susan;Jungbluth, Heinz
恶性高热是一种潜在致命的高代谢疾病，由卤代麻醉药和肌肉松弛剂琥珀酰胆碱在遗传易感个体中引发。大约50%的易感个体携带RYR1（编码ryanodine受体1型（RYR1））的显性功能获得突变，尽管他们的肌肉功能正常，没有明显的临床症状。RyR1主要存在于骨骼肌中，但在免疫和平滑肌细胞中的含量也较低，这表明RyR1突变的影响范围可能比之前怀疑的要大。轻度出血异常已被描述为恶性高热患者携带功能获得性RYR1突变。我们试图确定这种症状的频率和分子基础。我们发现一些具有特异性RYR1突变的患者有异常高的出血评分，而他们的健康亲属没有。具有恶性高热易感性RYR1突变Y522S （MHS RYR1(Y522S)）的敲入小鼠比其野生型幼崽出血时间更长。RYR1（Y522S）敲入小鼠的初级血管平滑肌细胞表现出更高频率的质下Ca2+火花，导致更多的负静息膜电位。RYR1（Y522S）小鼠和1例患者的出血缺陷通过RYR1拮抗剂丹曲林治疗得到逆转，ryanodine或丹曲林阻断了MHS RYR1（Y522S）小鼠原发性血管平滑肌细胞中的Ca2+火花。因此，RYR1突变可能通过改变血管平滑肌细胞功能导致出血延长。出血表型的可逆性强调了丹曲林在治疗此类出血性疾病中的潜在治疗价值。
Malignant hyperthermia is a potentially fatal hypermetabolic disorder triggered by halogenated anesthetics and the myorelaxant succinylcholine in genetically predisposed individuals. About 50% of susceptible individuals carry dominant, gain-of-function mutations in RYR1 [which encodes ryanodine receptor type 1 (RyR1)], though they have normal muscle function and no overt clinical symptoms. RyR1 is predominantly found in skeletal muscle but also at lower amounts in immune and smooth muscle cells, suggesting that RYR1 mutations may have a wider range of effects than previously suspected. Mild bleeding abnormalities have been described in patients with malignant hyperthermia carrying gain-of-function RYR1 mutations. We sought to determine the frequency and molecular basis for this symptom. We found that some patients with specific RYR1 mutations had abnormally high bleeding scores, whereas their healthy relatives did not. Knock-in mice with the malignant hyperthermia susceptibility RYR1 mutation Y522S (MHS RYR1(Y522S)) had longer bleeding times than their wildtype littermates. Primary vascular smooth muscle cells from RYR1(Y522S) knock-in mice exhibited a higher frequency of subplasmalemmal Ca2+ sparks, leading to a more negative resting membrane potential. The bleeding defect of RYR1(Y522S) mice and of one patient was reversed by treatment with the RYR1 antagonist dantrolene, and Ca2+ sparks in primary vascular smooth muscle cells from the MHS RYR1(Y522S) mice were blocked by ryanodine or dantrolene. Thus, RYR1 mutations may lead to prolonged bleeding by altering vascular smooth muscle cell function. The reversibility of the bleeding phenotype emphasizes the potential therapeutic value of dantrolene in the treatment of such bleeding disorders.