RNAi-based inhibition specific for mutant alleles in autosomal dominant diseases: Sequence-dependent and -independent discrimination of mutant and wild-type alleles by siRNA

Abstract

In autosomal recessive diseases, the protein products of the mutant genes are either not expressed (null mutation) or lose their function. In contrast, in autosomal dominant diseases the protein encoded by the mutant gene usually induces disease due to its toxic property. This "gain of toxic function" of a mutant protein is predicted to cause cell death in autosomal-dominant neurodegenerative diseases characterized by a missense point mutation, such as occurs in familial amyotrophic lateral sclerosis, familial Alzheimer disease, prion-induced disease, familial Parkinson's disease, and familial amyloid neuropathy. For all these familial diseases, a rational approach to therapy is to develop a method to specifically eliminate the aberrant protein by RNA interference (RNAi), even if the various mechanisms of cell death are unknown.