Dominant-negative mutation

Barroso I et al. Dominant negative mutations in human PPAR-y associated with severe insulin resistance, diabetes melli-tus and hypertension. Nature 1999 402 880-883. 

Vottero A, Kino T, Combe H, Lecomte P, Chrousos GP. (2002) A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with pl60 steroid receptor coactivators. J Clin Endocrinol Metab. 87, 2658-2667. 

The induction of a loss or reduction of specific function by transgene expression is not trivial and has found restricted applications. However, a few interesting concepts have been realized overexpression of a receptor to reduce free ligand (Hofmann et al., 1988) expression of transgenes encoding dominant negative mutations expression of antisense RNA (or a ribozyme) or expression of a toxic polypeptide. These latter concepts are discussed in more detail. 

Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ, Chatterjee VK, O Rahilly S. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 1999 402(6764) 880-3. 

I. Barroso, M. Gurnell, V. E. F. Crowley, M. Agostini, J. W, Schwabe, M. A. Soos, et al. Dominant negative mutations in human PPARy associated with severe insulin resitance, diabetes mellitus and hypertension. Nature, 402, 880-883, 1999. 

Plumpton M, McGarvey M, Beggs JD. A dominant negative mutation in the conserved RNA helicase motif SAT causes splicing factor PRP2 to stall in spliceosomes. EMBO J. 1994 13 879-887. Kim SH, Smith J, Claude A, Lin RJ. The purified yeast pre-mRNA sphcing factor PRP2 is an RNA-dependent NTPase. EMBO J. 1992 11 2319-2326. 

Schwer B, Guthrie C. A dominant negative mutation in a spliceo-somal ATPase affects ATP hydrolysis but not binding to the spliceosome. Mol. Cell Biol. 1992 12 3540-3547. 

P. Reddy and S. Hahn. Dominant negative mutations in yeast TFIID define a bipartite DNA-binding region. Cell 65 (1991) 349-57. 

The importance of PPARy in insulin sensitivity was confirmed with the finding, in Cambridge, of two families presenting with severe insuUn resistance in whom rare mutations of the PPARy gene caused loss of PPARy activity (Barroso 1, Gumell M, Crowley VE, et al 1989 Dominant negative mutations in human PPARy associated with severe insulin resistance, diabetes meUitus and hypertension. Nature 402 880-882.)... 

Two methods for functionally Inactivating a gene without altering the gene sequence are by dominant negative mutations and RNA Interference (RNAl). Describe how each method can Inhibit expression of a gene. 

Loss of function or dominant negative mutations in p53 have been found in a majority of human cancers. It is thought that the normal function of p53 is to cause cell-cycle arrest when DNA damage exists in cells about to enter S phase and undergo DNA replication. A defect in p53 function would allow damaged DNA to be replicated, which could result in profound genetic alterations. 

O. Rajanayagam, K.T. Games, S.H. Levinson, H.E. Xu, J.W.R. Schwabe, T.M. Willson, S. O Rahilly, V.K. Chatterjee, Tyrosine Agonists reverse the molecular defects associated with dominant-negative mutations in human peroxisome proliferator-activated receptor gamma, Endocrinology 2004, 145, 1527-1538. 

A significant proportion of all cancers result from mutations in cellular proto-oncogenes. Nearly half of these cancers contain point mutations in the tumor-suppressor gene, p53. The ability of an siRNA compound to discriminate between wild-type (WT) and mutated forms of p53 mRNA allowed for the specific knockdown of a dominant-negative mutation, resulting in an inhibition of tumor growth and restoration of WT protein function [68]. 

Kasahara, Y., Kaneko, H., Fukao, T., Terada, T., Asano, T., Kasahara, K., and Kondo, N. (2003). Hyper-IgM syndrome with putative dominant negative mutation in activation-induced cytidine deaminase. / Allergy Clin. Immunol. 112, 755-760. 

Luo, JM, Y oshida, H, Komura, S, Ohishi, N, Pan, L, Shigeno, K, Hanamura, I, Miura, K, lida, S, Ueda, R, Naoe, T, Akao, Y, Ohno, R and Ohnishi, K (2003) Possible dominant-negative mutation of the SHIP gene in acute myeloid leukemia. Leukemia, 17,1-8. 

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