PMS1 protein homolog 1 (PMS1) (PMS1)

PMS1 protein homolog 1 (PMS1) is a member of the MutL homolog family and a vital component of the eukaryotic DNA mismatch repair (MMR) system (UniProt P54277). It functions primarily by forming a heterodimer with MLH1, known as MutLβ, which participates in the recognition and repair of DNA base-pair mismatches and insertion-deletion loops generated during DNA replication (GeneCards; Wikipedia). Beyond its canonical role in maintaining genomic stability, PMS1 has recently emerged as a significant therapeutic target for Huntington's disease and other trinucleotide repeat expansion disorders (Nature Communications, 2024, 15:3182). Research indicates that PMS1 is a key driver of somatic CAG repeat expansion, and its downregulation can slow the progression of these neurodegenerative conditions (Nature Communications, 2024, 15:3182). Small-molecule splice modulators, including branaplam and risdiplam, have been shown to target PMS1 by inducing the inclusion of a premature stop codon-containing pseudoexon, leading to reduced protein expression (BioWorld, 2025; Nature Communications, 2024). While therapeutic modulation of PMS1 offers a novel approach to treating repeat expansion diseases, it also presents challenges such as the potential for increased systemic mutation rates and an associated risk of malignancies like Lynch syndrome (GeneCards; PubMed 8128251).

Other names

PMSL1HNPCC3MLH2hPMS1Postmeiotic segregation increased 1Mismatch repair system component PMS1

Splice modulation via the induction of a frame-shifting pseudoexon containing a premature stop codon, leading to the downregulation of PMS1 protein levels (Nature Communications, 2024, 15:3182; BioWorld, 2025).