Novel mutations identified in EIF2B5 gene in Kashmiri patients as susceptibility factor for multiple sclerosis.

White matter disease refers to a set of diseases that affect the white matter of the brain and all of which have different consequences on brain function. Most of the studies have shown that it results from the defects during protein synthesis, with the gene defects in EIF2B1–5, encoding the five subunits of eukaryotic translation initiation factor 2B (eIF2B) α, β, γ, δ and ε, respectively. eIF2B plays a crucial role in protein translation and its regulation under different conditions. The previous studies have shown that mutations in five subunits of eIF2B cause white matter disease of the brain and thus EIF2B is the main culprit in development of white matter disease. In this study, the mutational screening of EIF2B5 gene encoding eIF2Bε was performed for the first time in 12 Kashmiri patients, each having a unique white matter disease condition. We found two novel missense mutations in EIF2B5: c.580A>G, p.Thr194Ala and c.611C>T, p.Ala204Val among the patients with demyelinating disease (multiple sclerosis), but no mutation was found in other patients. In conclusion our study suggests involvement of the EIF2B5 gene in MS development, thus suggesting p.Thr194Ala to be a susceptibility factor for the development of multiple sclerosis.

Lipopolysaccharide, Mediator of Sepsis Enigma: Recognition and Signaling.

The outer leaflet of Gram-negative bacterial membrane contains a great amount of lipopolysaccharides, also known as endotoxins, which play a central role in the pathogenesis of sepsis and ultimately septic shock. Lipopolysaccharide (LPS) is potent inducer of acute sepsis or chronic inflammation. Sepsis can strike anyone, but is most likely to develop from infection associated with events such as pneumonia, trauma, surgery, and burns, or serious illnesses such as cancer and AIDS. In fact, people whose deaths are ascribed to complications of cancer, AIDS, or pneumonia, often actually die as a direct result of sepsis. Sepsis involves a complex interaction between bacterial toxins and the host immune system. LPS stimulates Toll-like receptor (TLR)-4 which leads to the formation and release of range of proinflammatory mediators which are essential for the potent immune response. The massive host response to this single bacterial pattern recognition molecule is sufficient to generate diffuse endothelial injury, tissue hypoperfusion, disseminated intravascular coagulation and refractory shock. LPS recognition involves LPS binding protein (LBP), CD14 ending up in TLR4/MD-2/LPS complex. The complex leads to activation of TLR4 and subsequent signaling cascade via two pathways i. e., myeloid differentiation protein 88 (MyD88)-dependent and TRIF-dependent. Here is a brief review of TLR4 signaling and LPS recognition biology with its impact if any on downstream pathways.