RNA-dominant disease

RNA-dominant diseases are characterized by deleterious mutations that typically result in degenerative disorders affecting various neurological, cardiovascular, and muscular functions. Studies have found that they arise from repetitive non-coding RNA sequences, also known as toxic RNA, which inhibit RNA-binding proteins leading to pathogenic effects. The most studied RNA-dominant diseases include, but are not limited to, myotonic dystrophy and fragile X-associated tremor/ataxia syndrome (FXTAS).

The cause of these diseases has been found to conventionally be expanded repetitions of CNG or NCNG nucleotide sequences in non-coding RNA. For example, myotonic dystrophy type 1 (DM1) results from the repetition of RNA base pairs CUG transcribed from a region of the DMPK gene, while myotonic dystrophy type 2 (DM2) is derived from an expanded CCUG sequence repeat. Similarly, FXTAS results from CGG repeats transcribed from a region in the FMR1 gene encoding protein, and spinocerebellar ataxia (SCA) results from CAG repetition transcribed in various genes. Furthermore, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have been found to develop from the repeated GGGGCC sequence transcribed from an intron in the C90RF72 gene. These toxic RNA sequences consist of a varying number of repeats and have been observed to construct intermolecular hairpin structures which slow their decay and allow them the functionality to interact with proteins inducing irregular splicing. It is generally noted that overall variation in the expression of affected genes and the number of repeat sequences of the RNA have little to do with the pathogenic consequences, but rather it is the gain of organizational and catalytic functions of the mutant RNA, which is similar to that of mutant proteins, that causes the toxicity.

Toxic RNA can lead to a vast range of medical effects including those of insulin resistance, tumors, muscular wasting seen in myotonic dystrophies, impairment of motor skills seen in FXTAS, a variety neurodegenerative syndromes, and more. Treatment has been suggested for some of these RNA-dominant diseases while others are still considered incurable.

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