Protein O-glucosyltransferase 1 (POGLUT1) activity is critical for the Notch signaling pathway, being one of the main enzymes responsible for the glycosylation of the extracellular domain of Notch receptors. A biallelic mutation in the POGLUT1 gene has been reported in one family as the cause of an adult-onset limb-girdle muscular dystrophy (LGMD R21; OMIM# 617232). As the result of a collaborative international effort, we have identified the first cohort of 15 patients with LGMD R21, from nine unrelated families coming from different countries, providing a reliable phenotype-genotype and mechanistic insight. Patients carrying novel mutations in POGLUT1 all displayed a clinical picture of limb-girdle muscle weakness. However, the age at onset was broadened from adult to congenital and infantile onset. Moreover, we now report that the unique muscle imaging pattern of "inside-to-outside" fatty degeneration observed in the original cases is indeed a defining feature of POGLUT1 muscular dystrophy. Experiments on muscle biopsies from patients revealed a remarkable and consistent decrease in the level of the NOTCH1 intracellular domain, reduction of the pool of satellite cells (SC), and evidence of α-dystroglycan hypoglycosylation. In vitro biochemical and cell-based assays suggested a pathogenic role of the novel POGLUT1 mutations, leading to reduced enzymatic activity and/or protein stability. The association between the POGLUT1 variants and the muscular phenotype was established by in vivo experiments analyzing the indirect flight muscle development in transgenic Drosophila, showing that the human POGLUT1 mutations reduced its myogenic activity. In line with the well-known role of the Notch pathway in the homeostasis of SC and muscle regeneration, SC-derived myoblasts from patients' muscle samples showed decreased proliferation and facilitated differentiation. Together, these observations suggest that alterations in SC biology caused by reduced Notch1 signaling result in muscular dystrophy in LGMD R21 patients, likely with additional contribution from α-dystroglycan hypoglycosylation. This study settles the muscular clinical phenotype linked to POGLUT1 mutations and establishes the pathogenic mechanism underlying this muscle disorder. The description of a specific imaging pattern of fatty degeneration and muscle pathology with a decrease of α-dystroglycan glycosylation provides excellent tools which will help diagnose and follow up LGMD R21 patients.

中文翻译：

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POGLUT1双等位基因突变导致卫星细胞减少，α-dystroglycan低糖基化和独特的放射学模式引起的肌病。

蛋白O-葡萄糖基转移酶1（POGLUT1）的活性对于Notch信号通路至关重要，它是负责Notch受体胞外域糖基化的主要酶之一。在一个家族中已经报道了POGLUT1基因中的双等位基因突变是成人发作的肢带肌肉萎缩症的原因（LGMD R21； OMIM＃617232）。通过国际合作的结果，我们确定了来自不同国家的9个无关家庭的15名LGMD R21患者的首批研究，他们提供了可靠的表型-基因型和机制研究。在POGLUT1中携带新突变的患者均显示肢带肌肉无力的临床表现。但是，发病年龄从成人扩大到先天性和婴儿期。此外，我们现在报告，在原始病例中观察到的“由内而外”脂肪变性的独特肌肉成像模式确实是POGLUT1肌营养不良症的定义特征。对患者进行肌肉活检的实验显示，NOTCH1细胞内结构域水平显着且持续下降，卫星细胞（SC）池减少，并且存在α-营养不良性糖基低糖基化的证据。体外生化和基于细胞的测定表明，新型POGLUT1突变具有致病作用，导致酶活性和/或蛋白质稳定性降低。通过体内实验分析转基因果蝇中间接飞行肌肉的发育，建立了POGLUT1变体与肌肉表型之间的关联，表明人POGLUT1突变降低了其肌原性活性。与Notch通路在SC的稳态和肌肉再生中的众所周知的作用一致，来自患者肌肉样品的SC衍生的成肌细胞显示出增殖减少并促进了分化。在一起，这些观察结果表明，Notch1信号减少引起的SC生物学改变导致LGMD R21患者的肌肉营养不良，可能是α-营养不良糖基糖基化的额外贡献。这项研究解决了与POGLUT1突变相关的肌肉临床表型，并建立了这种肌肉疾病的致病机制。脂肪变性和肌肉病理学的特定成像模式的描述以及α-dystroglycan糖基化作用的减少提供了出色的工具，将有助于诊断和随访LGMD R21患者。