Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404, Illkirch, France.
Inserm U1258, Illkirch, France.
Acta Neuropathol Commun. 2019 Aug 27;7(1):138. doi: 10.1186/s40478-019-0781-8.
Recessive mutations in PYROXD1, encoding an oxidoreductase, were recently reported in families with congenital myopathy or limb-girdle muscular dystrophy. Here we describe three novel PYROXD1 families at the clinical, histological, and genetic level. Histological analyses on muscle biopsies from all families revealed fiber size variability, endomysial fibrosis, and muscle fibers with multiple internal nuclei and cores. Further characterization of the structural muscle defects uncovered aggregations of myofibrillar proteins, and provided evidence for enhanced oxidative stress. Sequencing identified homozygous or compound heterozygous PYROXD1 mutations including the first deep intronic mutation reinforcing a cryptic donor splice site and resulting in mRNA instability through exonisation of an intronic segment. Overall, this work expands the PYROXD1 mutation spectrum, defines and specifies the histopathological hallmarks of the disorder, and indicates that oxidative stress contributes to the pathomechanism. Comparison of all new and published cases uncovered a genotype/phenotype correlation with a more severe and early-onset phenotypic presentation of patients harboring splice mutations resulting in reduced PYROXD1 protein levels compared with patients carrying missense mutations.
PYROXD1 编码一种氧化还原酶，其隐性突变最近在先天性肌病或肢带型肌营养不良症的家族中被报道。在此，我们在临床、组织学和遗传学水平上描述了三个新的 PYROXD1 家系。对所有家系的肌肉活检组织进行的组织学分析显示纤维大小变异性、内肌膜纤维化和具有多个内部核和核仁的肌纤维。对结构肌缺陷的进一步特征分析揭示了肌原纤维蛋白的聚集，并提供了氧化应激增强的证据。测序确定了纯合子或复合杂合 PYROXD1 突变，包括第一个深内含子突变，增强了一个隐蔽的供体位点剪接，并通过内含子片段的外显子化导致 mRNA 不稳定性。总体而言，这项工作扩展了 PYROXD1 突变谱，定义和具体说明了该疾病的组织病理学特征，并表明氧化应激有助于发病机制。对所有新病例和已发表病例的比较揭示了一种基因型/表型相关性，与携带剪接突变的患者相比，携带错义突变的患者具有更严重和更早发病的表型表现，导致 PYROXD1 蛋白水平降低。
