Genotype-phenotype correlations in recessive RYR1-related myopathies
Genotype-phenotype correlations in recessive RYR1-related myopathies
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DOI：
10.1186/1750-1172-8-117
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发表时间：
2013-08-06
影响因子：
3.7
通讯作者：
Dowling, James J.
中科院分区：
文献类型：
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作者：
Amburgey, Kimberly;Bailey, Angela;Dowling, James J.
背景：RYR1基因突变通常与核心肌病相关，是先天性肌病最常见的病因。显性突变最常与中央核心疾病和恶性高热相关，基因型-表型模式已从这些突变的研究中出现，有助于理解疾病的发病机制。最近可用的整个RYR1编码序列的基因检测，导致了显着扩大在核心肌病和其他先天性肌病的隐性突变的识别。迄今为止，没有明确的模式已被确定在这些隐性突变，虽然没有系统的检查尚未performed.Methods：在这项研究中，我们调查了一个大的未发表的（n = 14）和以前报道的（n = 92）隐性RYR1 cases. Results：这个队列的整体检查显示近50%的情况下，非核心肌病相关的基因型-表型相关性。我们最重要的发现是，亚型突变（预期减少RyR1表达的突变）在具有严重临床表型的患者中富集。我们还确定，亚型突变更有可能在非中央核心肌病中遇到。与非亚纯型突变的位置分析，我们发现，错义突变一般富集在MH/CCD热点，特别是富集在选择性过滤器的通道pore.Conclusions：这些结果支持一个假设，即蛋白质功能的损失是一个关键的预测疾病参数。此外，他们认为RyR1表达降低可能决定了非核心相关的病理学，尽管蛋白表达的数据有限，应该在更大的队列中得到证实。最后，研究结果表明，通过通道孔的异常离子电导在隐性核心肌病的发病机制。总的来说，我们的研究结果代表了隐性RYR1肌病基因型-表型关联的综合分析。
Background: RYR1 mutations are typically associated with core myopathies and are the most common overall cause of congenital myopathy. Dominant mutations are most often associated with central core disease and malignant hyperthermia, and genotype-phenotype patterns have emerged from the study of these mutations that have contributed to the understanding of disease pathogenesis. The recent availability of genetic testing for the entire RYR1 coding sequence has led to a dramatic expansion in the identification of recessive mutations in core myopathies and other congenital myopathies. To date, no clear patterns have been identified in these recessive mutations, though no systematic examination has yet been performed.Methods: In this study, we investigated genotype-phenotype correlations in a large combined cohort of unpublished (n = 14) and previously reported (n = 92) recessive RYR1 cases.Results: Overall examination of this cohort revealed nearly 50% of cases to be non-core myopathy related. Our most significant finding was that hypomorphic mutations (mutations expected to diminish RyR1 expression) were enriched in patients with severe clinical phenotypes. We also determined that hypomorphic mutations were more likely to be encountered in non-central core myopathies. With analysis of the location of non-hypomorphic mutations, we found that missense mutations were generally enriched in the MH/CCD hotspots and specifically enriched in the selectivity filter of the channel pore.Conclusions: These results support a hypothesis that loss of protein function is a key predictive disease parameter. In addition, they suggest that decreased RyR1 expression may dictate non-core related pathology though, data on protein expression was limited and should be confirmed in a larger cohort. Lastly, the results implicate abnormal ion conductance through the channel pore in the pathogenesis in recessive core myopathies. Overall, our findings represent a comprehensive analysis of genotype-phenotype associations in recessive RYR1-myopathies.