Bi‐allelic variants in VWA1, encoding Von Willebrand Factor A domain containing 1 protein localized to the extracellular matrix (ECM), were linked to a neuromuscular disorder with manifestation in child‐ or adulthood. Clinical findings indicate a neuromyopathy presenting with muscle weakness. Given that pathophysiological processes are still incompletely understood, and biomarkers are still missing, we aimed to identify blood biomarkers of pathophysiological relevance: white blood cells (WBC) and plasma derived from six VWA1‐patients were investigated by proteomics. Four proteins, BET1, HNRNPDL, NEFM and PHGDH, known to be involved in neurological diseases and dysregulated in WBC were further validated by muscle‐immunostainings unravelling HNRNPDL as a protein showing differences between VWA1‐patients, healthy controls and patients suffering from neurogenic muscular atrophy and BICD2‐related neuromyopathy. Immunostaining studies of PHGDH indicate its involvement in apoptotic processes via co‐localisation with caspase‐3. NEFM showed an increase in cells within the ECM in biopsies of all patients studied. Plasma proteomics unravelled dysregulation of 15 proteins serving as biomarker candidates among which a profound proportion of increased ones (6/11) are mostly related to antioxidative processes and have even partially been described as blood biomarkers for other entities of neuromuscular disorders before. CRP elevated in plasma also showed an increase in the extracellular space of VWA1‐mutant muscle. Results of our combined studies for the first time describe pathophysiologically relevant biomarkers for VWA1‐related neuromyopathy and suggest that VWA1‐patient derived blood might hold the potential to study disease processes of clinical relevance, an important aspect for further preclinical studies.

中文翻译：

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VWA1 相关神经肌病的蛋白质组学研究提供了新的病理生理学见解和血液生物标志物的定义

双等位基因变异体大众WA1，编码血管性血友病因子 A 结构域，含有 1 个位于细胞外基质 (ECM) 的蛋白质，与儿童或成年期表现的神经肌肉疾病有关。临床结果表明神经肌病表现为肌肉无力。鉴于病理生理过程仍不完全了解，并且生物标志物仍然缺失，我们旨在识别与病理生理学相关的血液生物标志物：白细胞 (WBC) 和源自六种细胞的血浆大众WA1‐通过蛋白质组学对患者进行研究。四种蛋白质，BET1、HNRNPDL、NEFM 和 PHGDH，已知与神经系统疾病有关并在 WBC 中失调，通过肌肉免疫染色进一步验证，揭示了 HNRNPDL 作为一种蛋白质，显示出大众WA1‐患者、健康对照者和患有神经源性肌肉萎缩症的患者BICD2相关神经肌病。 PHGDH 的免疫染色研究表明它通过与 caspase-3 共定位参与细胞凋亡过程。 NEFM 显示所有研究患者的活检中 ECM 内的细胞有所增加。血浆蛋白质组学揭示了 15 种作为候选生物标志物的蛋白质的失调，其中很大一部分增加的蛋白质 (6/11) 主要与抗氧化过程有关，甚至之前部分被描述为其他神经肌肉疾病实体的血液生物标志物。血浆中 CRP 升高也表明细胞外空间增加大众WA1‐突变肌肉。我们的联合研究结果首次描述了病理生理学相关的生物标志物大众WA1相关的神经肌病并表明大众WA1‐患者来源的血液可能具有研究临床相关疾病过程的潜力，这是进一步临床前研究的一个重要方面。