Department of Biotechnology, Chaudhary Devi Lal University, Sirsa 125055, India.
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India.
Genes (Basel). 2023 Feb 24;14(3):567. doi: 10.3390/genes14030567.
The GNE-associated V727M mutation is one of the most prevalent ethnic founder mutations in the Asian HIBM cohort; however, its role in inducing disease phenotype remains largely elusive. In this study, the function of this hotspot mutation was profoundly investigated. For this, V727M mutation-specific altered expression profile and potential networks were explored. The relevant muscular disorder-specific in vivo studies and patient data were further analyzed, and the key altered molecular pathways were identified. Our study found that the GNEV727M mutation resulted in a deregulated lincRNA profile, the majority of which (91%) were associated with a down-regulation trend. Further, in silico analysis of associated targets showed their active role in regulating Wnt, TGF-β, and apoptotic signaling. Interestingly, COL6a3 was found as a key target of these lincRNAs. Further, GSEA analysis showed HIBM patients with variable COL6A3 transcript levels have significant alteration in many critical pathways, including epithelial-mesenchymal-transition, myogenesis, and apoptotic signaling. Interestingly, 12 of the COL6A3 coexpressed genes also showed a similar altered expression profile in HIBM. A similar altered trend in COL6A3 and coexpressed genes were found in in vivo HIBM disease models as well as in multiple other skeletal disorders. Thus, the COL6A3-specific 13 gene signature seems to be altered in multiple muscular disorders. Such deregulation could play a pivotal role in regulating many critical processes such as extracellular matrix organization, cell adhesion, and skeletal muscle development. Thus, investigating this novel COL6A3-specific 13 gene signature provides valuable information for understanding the molecular cause of HIBM and may also pave the way for better diagnosis and effective therapeutic strategies for many muscular disorders.
GNE 相关的 V727M 突变是亚洲 HIBM 队列中最常见的种族起源突变之一；然而，其在诱导疾病表型中的作用在很大程度上仍未被揭示。在本研究中，深入研究了这一热点突变的功能。为此，探索了 V727M 突变特异性的改变表达谱和潜在网络。进一步分析了相关的肌肉疾病特定的体内研究和患者数据，并确定了关键的改变分子途径。我们的研究发现，GNEV727M 突变导致 lincRNA 谱失调，其中大多数（91%）与下调趋势相关。此外，相关靶标分析表明它们在调节 Wnt、TGF-β和凋亡信号方面发挥积极作用。有趣的是，COL6a3 被发现是这些 lincRNA 的关键靶标。进一步的 GSEA 分析显示，COL6A3 转录本水平变化的 HIBM 患者在许多关键途径中存在显著改变，包括上皮-间充质转化、成肌和凋亡信号。有趣的是，COL6A3 的 12 个共表达基因在 HIBM 中也表现出相似的改变表达谱。在 HIBM 疾病模型以及其他多种骨骼疾病中也发现了 COL6A3 和共表达基因的相似改变趋势。因此，COL6A3 特异性的 13 基因特征似乎在多种肌肉疾病中发生改变。这种失调可能在调节细胞外基质组织、细胞黏附和骨骼肌肉发育等许多关键过程中发挥关键作用。因此，研究这一新的 COL6A3 特异性的 13 基因特征为理解 HIBM 的分子原因提供了有价值的信息，也为许多肌肉疾病的更好诊断和有效治疗策略铺平了道路。
