Osteitis Deformans
Return to Library
|
Free Osteitis Deformans Articles |
|
|
|
|
Studies from University of Nottingham in the area of osteitis deformans described
2009 JUN 2 - (NewsRx.com) -- "Mutations affecting the ubiquitin-associated (UBA) domain of sequestosome 1 (SQSTM1/p62) are commonly found in Paget's disease of bone (PDB) and impair SQSTM1's ability to bind ubiquitin, resulting in dysregulated NF-kappa B signaling. In contrast, non-UBA domain mutations are rarer, and little is known about how they manifest their effects," researchers in Nottingham, the United Kingdom report. "We present the first characterization at the molecular, cellular, and functional level of a non-UBA domain missense mutation (A381V) of SQSTM1. Direct sequencing of exon 7 of the SQSTM1 gene in all Italian PDB patient detected a heterozygous C to T transversion at position 1182, resulting in all alanine to valine substitution at codon 381. Pull-down assays showed the non-UBA region of SQSTM1. that contains A381 is important in mediating ubiquitin-binding affinity and that the A381V mutation exerts weak negative effects on ubiquitin binding. Structural and binding analyses of longer UBA constructs containing A381, using NMR spectroscopy and circular dichroism, showed this region of the protein to be largely unstructured and confirmed its contribution to increased ubiquitin-binding, affinity. Co-transfections of U20S cells showed that the A381V mutant SQSTM1 co-localized with ubiquitin with a cellular phenotype indistinguishable from wildtype. Finally, effects of the wildtype and mutant SQSTM1 on NF-kappa B signaling were assessed in HEK293 cells co-transfected with an NF-kappa B luciferase reporter construct," wrote D. Najat and colleagues, University of Nottingham. The researchers concluded: "A381V mutant SQSTM1 produced a level of activation of NF-kappa B signaling greater than wildtype and similar to that of UBA domain mutants, indicating, that non-UBA and UBA domain mutations may exert their effects through a common mechanism involving dysregulated NF-kappa B signaling." Najat and colleagues published their study in the Journal of Bone and Mineral Research (Characterization of a Non-UBA Domain Missense Mutation of Sequestosome 1 (SQSTM1) in Paget's Disease of Bone. Journal of Bone and Mineral Research, 2009;24(4):632-642). For additional information, contact R. Layfield, University of Nottingham, School Medical, School Biomedical Science, Nottingham NG7 2UH, UK. Publisher contact information for the Journal of Bone and Mineral Research is: American Society Bone & Mineral Research, 2025 M St., N W, Ste. 800, Washington, DC 20036-3309, USA. Keywords: United Kingdom, Nottingham, Bone, Osteitis Deformans, Paget Disease, University of Nottingham. This article was prepared by Life Science Weekly editors from staff and other reports. Copyright 2009, Life Science Weekly via NewsRx.com.
|
