PDF(Sci-hub)
Abstract：
Pathogenic variations in the gene encoding the skeletal muscle ryanodine receptor (RyR1) are associated with malignant hyperthermia (MH) susceptibility, a life-threatening hypermetabolic condition and RYR1-related myopathies (RYR1-RM), a spectrum of rare neuromuscular disorders. In RYR1-RM, intracellular calcium dysregulation, post-translational modifications, and decreased protein expression lead to a heterogenous clinical presentation including proximal muscle weakness, contractures, scoliosis, respiratory insufficiency, and ophthalmoplegia. Preclinical model systems of RYR1-RM and MH have been developed to better understand underlying pathomechanisms and test potential therapeutics.
We conducted a comprehensive scoping review of scientific literature pertaining to RYR1-RM and MH preclinical model systems in accordance with the PRISMA Scoping Reviews Checklist and the framework proposed by Arksey and O\'Malley. Two major electronic databases (PubMed and EMBASE) were searched without language restriction for articles and abstracts published between January 1, 1990 and July 3, 2019.
Our search yielded 5049 publications from which 262 were included in this review. A majority of variants tested in RYR1 preclinical models were localized to established MH/central core disease (MH/CCD) hot spots. A total of 250 unique RYR1 variations were reported in human/rodent/porcine models with 95% being missense substitutions. The most frequently reported RYR1 variant was R614C/R615C (human/porcine total n = 39), followed by Y523S/Y524S (rabbit/mouse total n = 30), I4898T/I4897T/I4895T (human/rabbit/mouse total n = 20), and R163C/R165C (human/mouse total n = 18). The dyspedic mouse was utilized by 47% of publications in the rodent category and its RyR1-null (1B5) myotubes were transfected in 23% of publications in the cellular model category. In studies of transfected HEK-293 cells, 57% of RYR1 variations affected the RyR1 channel and activation core domain. A total of 15 RYR1 mutant mouse strains were identified of which ten were heterozygous, three were compound heterozygous, and a further two were knockout. Porcine, avian, zebrafish, C. elegans, canine, equine, and drosophila model systems were also reported.
Over the past 30 years, there were 262 publications on MH and RYR1-RM preclinical model systems featuring more than 200 unique RYR1 variations tested in a broad range of species. Findings from these studies have set the foundation for therapeutic development for MH and RYR1-RM.
We conducted a comprehensive scoping review of scientific literature pertaining to RYR1-RM and MH preclinical model systems in accordance with the PRISMA Scoping Reviews Checklist and the framework proposed by Arksey and O\'Malley. Two major electronic databases (PubMed and EMBASE) were searched without language restriction for articles and abstracts published between January 1, 1990 and July 3, 2019.
Our search yielded 5049 publications from which 262 were included in this review. A majority of variants tested in RYR1 preclinical models were localized to established MH/central core disease (MH/CCD) hot spots. A total of 250 unique RYR1 variations were reported in human/rodent/porcine models with 95% being missense substitutions. The most frequently reported RYR1 variant was R614C/R615C (human/porcine total n = 39), followed by Y523S/Y524S (rabbit/mouse total n = 30), I4898T/I4897T/I4895T (human/rabbit/mouse total n = 20), and R163C/R165C (human/mouse total n = 18). The dyspedic mouse was utilized by 47% of publications in the rodent category and its RyR1-null (1B5) myotubes were transfected in 23% of publications in the cellular model category. In studies of transfected HEK-293 cells, 57% of RYR1 variations affected the RyR1 channel and activation core domain. A total of 15 RYR1 mutant mouse strains were identified of which ten were heterozygous, three were compound heterozygous, and a further two were knockout. Porcine, avian, zebrafish, C. elegans, canine, equine, and drosophila model systems were also reported.
Over the past 30 years, there were 262 publications on MH and RYR1-RM preclinical model systems featuring more than 200 unique RYR1 variations tested in a broad range of species. Findings from these studies have set the foundation for therapeutic development for MH and RYR1-RM.
摘要：
编码骨骼肌ryanodine受体（RyR1）的基因的致病变异与恶性高热（MH）易感性有关，危及生命的高代谢性疾病和RYR1相关肌病（RYR1-RM），一系列罕见的神经肌肉疾病。在RYR1-RM中，细胞内钙失调，翻译后修饰，蛋白表达减少导致异质性临床表现，包括近端肌无力，挛缩,脊柱侧弯,呼吸功能不全,和眼肌麻痹。已经开发了RYR1-RM和MH的临床前模型系统，以更好地了解潜在的病理机制并测试潜在的治疗方法。
我们根据PRISMA范围审查清单和Arksey和O'Malley提出的框架，对与RYR1-RM和MH临床前模型系统相关的科学文献进行了全面的范围审查。在没有语言限制的情况下搜索了两个主要的电子数据库（PubMed和EMBASE），以查找1990年1月1日至2019年7月3日之间发表的文章和摘要。
我们的搜索产生了5049种出版物，其中262种被包括在这篇综述中。在RYR1临床前模型中测试的大多数变体被定位到建立的MH/中枢核心疾病(MH/CCD)热点。在人/啮齿动物/猪模型中报告了总共250种独特的RYR1变异,其中95%是错义取代。最常报道的RYR1变体是R614C/R615C（人/猪总n=39），其次是Y523S/Y524S（兔/鼠总n=30），I4898T/I4897T/I4895T（人/兔/小鼠总n=20），和R163C/R165C(人/小鼠总计n=18)。在啮齿动物类别中，有47％的出版物使用了病态小鼠，而在细胞模型类别中，有23％的出版物转染了RyR1-null（1B5）肌管。在转染HEK-293细胞的研究中，57%的RYR1变异影响RyR1通道和激活核心域。共鉴定出15个RYR1突变小鼠品系，其中10个为杂合，三个是复合杂合的，还有两个被击倒。猪,禽类,斑马鱼,C.秀丽隐杆线虫,犬,马,和果蝇模型系统也被报道。
在过去的30年里,关于MH和RYR1-RM临床前模型系统的出版物有262篇,在广泛的物种中测试了200多种独特的RYR1变异.这些研究的结果为MH和RYR1-RM的治疗开发奠定了基础。
我们根据PRISMA范围审查清单和Arksey和O'Malley提出的框架，对与RYR1-RM和MH临床前模型系统相关的科学文献进行了全面的范围审查。在没有语言限制的情况下搜索了两个主要的电子数据库（PubMed和EMBASE），以查找1990年1月1日至2019年7月3日之间发表的文章和摘要。
我们的搜索产生了5049种出版物，其中262种被包括在这篇综述中。在RYR1临床前模型中测试的大多数变体被定位到建立的MH/中枢核心疾病(MH/CCD)热点。在人/啮齿动物/猪模型中报告了总共250种独特的RYR1变异,其中95%是错义取代。最常报道的RYR1变体是R614C/R615C（人/猪总n=39），其次是Y523S/Y524S（兔/鼠总n=30），I4898T/I4897T/I4895T（人/兔/小鼠总n=20），和R163C/R165C(人/小鼠总计n=18)。在啮齿动物类别中，有47％的出版物使用了病态小鼠，而在细胞模型类别中，有23％的出版物转染了RyR1-null（1B5）肌管。在转染HEK-293细胞的研究中，57%的RYR1变异影响RyR1通道和激活核心域。共鉴定出15个RYR1突变小鼠品系，其中10个为杂合，三个是复合杂合的，还有两个被击倒。猪,禽类,斑马鱼,C.秀丽隐杆线虫,犬,马,和果蝇模型系统也被报道。
在过去的30年里,关于MH和RYR1-RM临床前模型系统的出版物有262篇,在广泛的物种中测试了200多种独特的RYR1变异.这些研究的结果为MH和RYR1-RM的治疗开发奠定了基础。
