Attri Shivangi, Sharma Vikas, Kumar Amit, Verma Chaitenya, Gahlawat Suresh Kumar
Department of Biotechnology, Chaudhary Devi Lal University, Sirsa, 440002, India.
General Facility, Centralized Core Research Facility, All India Institute of Medical Sciences, New Delhi, 110029, India.
Open Med (Wars). 2021 Nov 15;16(1):1733-1744. doi: 10.1515/med-2021-0391. eCollection 2021.
GNE gene-specific c.2179G>A(p.V727M) is a key alteration reported in patients with hereditary inclusion body myopathy (HIBM) and represents an ethnic founder mutation in the Indian cohort. However, the underlying role of this mutation in pathogenesis remains largely unknown. Thus, in this study, we aimed to access possible mechanisms of V727M mutation that could be leading to myopathy. We evaluated various tools to predict the effect of this mutation on pathogenicity, structural or possible interactions, that could induce myopathy. Our results propose that V727M mutation could induce deleterious effects or pathogenicity and affect the stability of GNE protein. Analysis of differential genes reported in the V727 mutant case suggests that it can affect GNE protein interaction with Myc-proto-oncogene (MYC) transcription factor. Our analysis also suggests a possible interaction between GNE ManNac-kinase domain with MYC protein at the C-terminal DNA-binding domain. MYC targets reported in skeletal muscles via ChIP-seq suggest that it plays a key role in regulating the expression of many genes reported differentially expressed in V727M-mutated HIBMs. We conclude that V727M mutation could alter the interaction of GNE with MYC thereby altering transcription of sialyltransferase and neuromuscular genes, thus understanding these effects could pave the way for developing effective therapies against HIBM.
GNE基因特异性的c.2179G>A（p.V727M）是遗传性包涵体肌病（HIBM）患者中报道的一种关键改变，在印度人群中代表一种族群奠基者突变。然而，这种突变在发病机制中的潜在作用仍 largely unknown。因此，在本研究中，我们旨在探究V727M突变可能导致肌病的机制。我们评估了各种工具来预测这种突变对致病性、结构或可能的相互作用的影响，这些影响可能诱发肌病。我们的结果表明，V727M突变可能诱导有害效应或致病性，并影响GNE蛋白的稳定性。对V727突变病例中报道的差异基因的分析表明，它可能影响GNE蛋白与Myc原癌基因（MYC）转录因子的相互作用。我们的分析还表明，GNE甘露糖激酶结构域与MYC蛋白在C末端DNA结合结构域可能存在相互作用。通过ChIP-seq在骨骼肌中报道的MYC靶点表明，它在调节许多在V727M突变的HIBM中差异表达的基因的表达中起关键作用。我们得出结论，V727M突变可能改变GNE与MYC的相互作用，从而改变唾液酸转移酶和神经肌肉基因的转录，因此了解这些影响可为开发针对HIBM的有效疗法铺平道路。
