The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca2+ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca2+-dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1-related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1-typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy.

中文翻译：

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与早发性肌张力减退和良性病程相关的复发性 RYR1 突变

兰尼碱受体 RyR1 是骨骼肌中主要的肌质网 Ca2+ 通道，是电刺激和依赖 Ca2+ 的肌肉收缩之间的连接纽带。RyR1 活性异常会损害正常的肌肉功能并导致各种人类疾病，包括恶性高热、中枢核心疾病和中央核肌病。然而，RYR1 是人类基因组中最大的基因之一，积累了大量意义不确定的错义变异 (VUS)，妨碍了许多患者和家属的有效分子诊断。在这里，我们描述了以前归类为 VUS 的复发性 RYR1 突变，并提供了支持其致病性的临床、组织学和遗传数据。杂合子 c.12083C>T (p. Ser4028Leu) 突变在来自 9 个不相关的先天性肌病家族的 13 名患者中发现，具有一致的临床表现，并且在主要家族中与疾病分离或从头发生。受影响的个体基本上表现出新生儿或婴儿期肌张力减退、运动里程碑延迟和不同于经典 RYR1 相关肌肉疾病的良性病程。肌肉活检显示非特异性组织学和超微结构发现，而 RYR1 典型核心和内部细胞核仅见于单个患者。总之，我们的数据证明了 RYR1 c.12083C>T (p.Ser4028Leu) 突变在非典型先天性肌病发展中的因果关系，在生命的最初几十年逐渐改善运动功能，