MutS homolog 3 pre-messenger RNA (MSH3 pre-mRNA) (MSH3 pre-mRNA)

MutS homolog 3 (MSH3) pre-messenger RNA is the primary transcript of the MSH3 gene, which encodes a protein essential for the DNA mismatch repair (MMR) pathway (UniProt P20447). The MSH3 protein specifically forms the "MutS-beta" complex with MSH2 to recognize and initiate the repair of large insertion-deletion loops (NIH/NCBI Gene: MSH3). In the context of neurodegenerative diseases like Huntington's disease (HD) and Myotonic Dystrophy, MSH3 has been identified as a major genetic modifier of somatic repeat expansion (Flower et al., 2019, Genetics in Medicine). This process involves the progressive lengthening of trinucleotide repeats in neurons, which is strongly correlated with earlier disease onset and increased severity (Lee et al., 2019, Nature Communications). Therapeutic strategies targeting the MSH3 pre-mRNA, such as antisense oligonucleotides (ASOs) or small molecule splicing modifiers, aim to reduce the levels of functional MSH3 protein (Tabrizi et al., 2020, Neuron). By lowering MSH3 expression, these therapies seek to stabilize CAG repeats and slow the progression of polyglutamine diseases (Goold et al., 2019, Nature Communications). For example, Skyhawk Therapeutics is developing SKY-0515, a small molecule designed to modify MSH3 pre-mRNA splicing to reduce protein levels (Skyhawk Therapeutics Pipeline). While reducing MSH3 is a promising approach, it presents a significant therapeutic challenge regarding the potential for increased genomic instability or cancer risk (NIH/NCBI Gene: MSH3).

Other names

MutS homolog 3 precursor RNAMismatch repair protein 1 pre-mRNADUP pre-mRNAMRP1 pre-mRNA

Splicing modulation to induce exon skipping or inclusion, and RNase H-mediated degradation of the pre-mRNA transcript.