POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern.
POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern.
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POGLUT1 双等位基因突变导致肌病，伴有卫星细胞减少、α-dystroglycan 糖基化低下和独特的放射学模式。
DOI：
10.1007/s00401-019-02117-6
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发表时间：
2020
影响因子：
12.7
通讯作者：
V
中科院分区：
文献类型：
--
作者：
Servián-Morilla,E;Cabrera-Serrano,M;Johnson,K;Pandey,A;Ito,A;Rivas,E;Chamova,T;Muelas,N;Mongini,T;Nafissi,S;Claeys,KG;Grewal,RP;Takeuchi,M;Hao,H;Bönnemann,C;LopesAbathNeto,O;Medne,L;Brandsema,J;Töpf,A;Taneva,A;V
蛋白O-葡糖基转移酶1（POGLUT 1）活性对于Notch信号通路至关重要，是负责Notch受体胞外结构域糖基化的主要酶之一。在一个家族中，POGLUT 1基因的双等位基因突变被报道为成人型肢带型肌营养不良症的病因（LGMD R21; OMIM# 617232）。作为国际合作的结果，我们已经确定了第一批15名LGMD R21患者，来自来自不同国家的9个无关家族，提供了可靠的表型-基因型和机制见解。携带POGLUT 1新突变的患者均表现出肢带肌无力的临床表现。然而，发病年龄从成人扩大到先天性和婴儿发病。此外，我们现在报告说，在最初的病例中观察到的独特的肌肉成像模式的“内到外”脂肪变性确实是POGLUT 1肌营养不良症的一个定义特征。对患者肌肉活检的实验显示，NOTCH 1细胞内结构域水平显著且一致地降低，卫星细胞（SC）池减少，以及α-肌营养不良蛋白聚糖低糖基化的证据。体外生物化学和基于细胞的分析表明新POGLUT 1突变的致病作用，导致酶活性和/或蛋白质稳定性降低。POGLUT 1变异体和肌肉表型之间的关联是通过分析转基因果蝇间接飞行肌发育的体内实验建立的，表明人类POGLUT 1突变降低了其生肌活性。与Notch途径在SC和肌肉再生的体内平衡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降低和促进分化。总之，这些观察结果表明，由Notch 1信号传导减少引起的SC生物学改变导致LGMD R21患者的肌营养不良，可能还有α-肌营养不良聚糖低糖基化的额外贡献。本研究确定了与POGLUT 1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。对脂肪变性和肌肉病理学的特定成像模式以及α-肌营养不良聚糖糖基化减少的描述提供了极好的工具，有助于诊断和随访LGMD R21患者。
ProteinO-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 thePOGLUT1gene 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 inPOGLUT1all 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 ofPOGLUT1muscular 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 novelPOGLUT1mutations, leading to reduced enzymatic activity and/or protein stability. The association between thePOGLUT1variants and the muscular phenotype was established by in vivo experiments analyzing the indirect flight muscle development in transgenicDrosophila, showing that the humanPOGLUT1mutations 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 toPOGLUT1mutations 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.