Mutation loss-of-function

On pharmacodynamic grounds, tumor resistance may be caused by such diverse mechanisms as the mutation or redundancy of topo II, the overexpression and preferred nuclear localization of proteasome a-type subunits (leading to a anomalous degradation of topo II), genetic deletion or loss-of-function mutations of p53, overexpression of ROS-detoxifying enzymes, overexpression of Bcl-2 (leading to a diminished cyt c release), etc. However, none of these factors would universally predict the development of anthracycline-resistance in a given tumor or another. 

Btk (Bruton s tyrosine kinase) is a phosphatidylinositol 3 -kinase sensitive cytoplasmic tyrosine kinase. Germline loss of function mutations of Btk cause X-linked agammaglobulinaemia in human and X-linked immunodeficiency in mice. 

Blanpain, C., Le Poul, E., Parma, J., Knoop, C., Detheux, M., Parmentier, M., Vassart, G. and Abramowicz, M.J. (2003) Serotonin 5-HT(2B) receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension. Cardiovascular Research, 60 (3), 518-528. 

Clinically unaffected skin in atopic dermatitis differs from normal skin the underlying barrier defect associated in more than 30% with filaggrin loss of function mutations first published in 2006 [4] leads to dry skin associated with a greater irritant skin response than in normal healthy skin. Microscopic studies revealed a sparse perivascular T cell infiltrate in unaffected atopic dermatitis skin that is not seen in normal healthy skin. 

As mentioned above, a subgroup of patients with atopic dermatitis has a filaggrin loss-of-function mutation Recently, it was shown that filaggrin expression is reduced in atopic dermatitis even in the absence of any mutation [29]. Keratinocytes differentiated in the presence of IL-4 and IL-13 exhibited significantly reduced filaggrin gene expression and neutralization of IL-4 and IL-13 improves skin barrier integrity [30]. This indicates that Th-2 lymphocytes directly contribute to the skin barrier defect in atopic dermatitis. 

Unlike tumor suppressors, in which loss-of-function mutations are required in both copies of the gene in a specific cell, a single gain-of-function mutation in a proto-oncogene is usually sufficient to give rise to cancer. 

Gene replacement therapy for loss of function mutations... 

Hofstra, R. M. W., Valdenaire, O., Arch, E., et al. (1999) A loss-of-function mutation in the endothelin-converting enzyme 1 (ECE-1) associated with Hirschsprung disease, cardiac defects, and autonomic dysfunction. Am. J. Hum. Genet. 64, 304-308. 

The biochemical defect In families exhibiting this syndrome is a loss-of-function mutation of the tumor suppressor gene, TP53, encoding p53. 

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