Zhou Haiyan, Jungbluth Heinz, Sewry Caroline A, Feng Lucy, Bertini Enrico, Bushby Kate, Straub Volker, Roper Helen, Rose Michael R, Brockington Martin, Kinali Maria, Manzur Adnan, Robb Stephanie, Appleton Richard, Messina Sonia, D'Amico Adele, Quinlivan Ros, Swash Michael, Müller Clemens R, Brown Susan, Treves Susan, Muntoni Francesco
Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Hospital, London W12 0NN.
Brain. 2007 Aug;130(Pt 8):2024-36. doi: 10.1093/brain/awm096. Epub 2007 May 4.
Dominant mutations in the skeletal muscle ryanodine receptor (RYR1) gene are well-recognized causes of both malignant hyperthermia susceptibility (MHS) and central core disease (CCD). More recently, recessive RYR1 mutations have been described in few congenital myopathy patients with variable pathology, including multi-minicores. Although a clinical overlap between patients with dominant and recessive RYR1 mutations exists, in most cases with recessive mutations the pattern of muscle weakness is remarkably different from that observed in dominant CCD. In order to characterize the spectrum of congenital myopathies associated with RYR1 mutations, we have investigated a cohort of 44 patients from 28 families with clinical and/or histopathological features suggestive of RYR1 involvement. We have identified 25 RYR1 mutations, 9 of them novel, including 12 dominant and 13 recessive mutations. With only one exception, dominant mutations were associated with a CCD phenotype, prominent cores and predominantly occurred in the RYR1 C-terminal exons 101 and 102. In contrast, the 13 recessive RYR1 mutations were distributed evenly along the entire RYR1 gene and were associated with a wide range of clinico-pathological phenotypes. Protein expression studies in nine cases suggested a correlation between specific mutations, RyR1 protein levels and resulting phenotype: in particular, whilst patients with dominant or recessive mutations associated with typical CCD phenotypes appeared to have normal RyR1 expression, individuals with more generalized weakness, multi-minicores and external ophthalmoplegia had a pronounced depletion of the RyR1 protein. The phenomenon of protein depletion was observed in some patients compound heterozygous for recessive mutations at the genomic level and silenced another allele in skeletal muscle, providing additional information on the mechanism of disease in these patients. Our data represent the most extensive study of RYR1-related myopathies and indicate complex genotype-phenotype correlations associated with mutations differentially affecting assembly and function of the RyR1 calcium release channel.
骨骼肌兰尼碱受体（RYR1）基因的显性突变是恶性高热易感性（MHS）和中央轴空病（CCD）的公认病因。最近，在少数具有不同病理表现（包括多微小核）的先天性肌病患者中发现了隐性RYR1突变。虽然显性和隐性RYR1突变患者之间存在临床重叠，但在大多数隐性突变病例中，肌无力模式与显性CCD中观察到的明显不同。为了描述与RYR1突变相关的先天性肌病谱，我们研究了来自28个家庭的44例患者，这些患者具有提示RYR1受累的临床和/或组织病理学特征。我们鉴定出25个RYR1突变，其中9个是新突变，包括12个显性突变和13个隐性突变。除了一个例外，显性突变与CCD表型、明显的轴空相关，并且主要发生在RYR1 C末端外显子101和102中。相比之下，13个隐性RYR1突变沿整个RYR1基因均匀分布，并与广泛的临床病理表型相关。对9例患者的蛋白质表达研究表明，特定突变、RyR1蛋白水平与所产生的表型之间存在相关性：特别是，与典型CCD表型相关的显性或隐性突变患者似乎具有正常的RyR1表达，而具有更广泛肌无力、多微小核和眼外肌麻痹的个体则有明显的RyR1蛋白耗竭。在一些基因组水平上为隐性突变复合杂合子且在骨骼肌中另一个等位基因沉默的患者中观察到了蛋白质耗竭现象，这为这些患者的疾病机制提供了更多信息。我们的数据代表了对RYR1相关肌病最广泛的研究，并表明与差异影响RyR1钙释放通道组装和功能的突变相关的复杂基因型-表型相关性。
