Disease-modifying genes

Dixon SJ, Stockwell BR (2009) Identifying druggable disease-modifying gene products. Curr Opinion Chem Biol 13 549-555... 

The new work has established that a neurodegenerative pathway leading from soluble to insoluble, filamentous a-synuclein is central to Lewy body diseases and multiple system atrophy. The development of experimental models of a-synucleinopathies has opened the way to the identification of the detailed mechanisms by which the formation of inclusions causes disease. These model systems have also made it possible to identify disease modifiers that may well lead to the development of the first mechanism-based therapies for these diseases. At a conceptual level, it will be important to understand whether a-synuclein has a role to play in disorders, such as autosomal-recessive juvenile forms of parkinsonism caused by mutations in the Parkin, DJ-1 and PINK-1 genes, or whether there are entirely separate mechanisms by which the dopaminergic nerve cells of the substantia nigra degenerate in Parkinson s disease and in inherited disorders with parkinsonism. 

While certain behavioral and nonbehavioral diseases are believed to be monogenic, diseases such as Huntington s, cystic fibrosis, Marfan, and Hirschsprung result in the specified disease, and the outward appearance or result (phenotype) of the disease varies between individuals. For instance, for Marfan syndrome, there is a level below which the mutant protein does not exhibit itself in an outward manner. Most of these diseases have modifier genes that cause modifications in the outward demonstration of the disease and play a key role in the clinical symptoms. Further, the particular metabolic pathways are often varied, with several of the steps being important and the importance of each mechanistic pathway may differ with every individual. 

With completion of the human genome project, the functional and positional cloning of Mendelian traits and diseases can become fairly routine (2). Yet, considerable work still lies ahead even with Mendelian diseases document worldwide variation in mutations, identify the effects of modifier genes on heterogeneity with respect to age of onset and severity, obtain accurate measurements of the penetrance values of different allelic mutations, study the effects of environmental factors on disease expression, and develop appropriate therapies. 

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